Aging-, obesity-, and diabetes-related sarcopenia: Pathogenesis and interventions

Abstract

As global aging accelerates, sarcopenia has become an increasingly important public health concern. Although typically recognized as an age-related condition, sarcopenia can develop and progress more rapidly under certain pathological conditions, such as obesity and type 2 diabetes. With the ongoing advancement of related research, the mechanisms underlying sarcopenia are being progressively elucidated. Management strategies include both nonpharmacological and pharmacological interventions. Resistance exercise is currently regarded as one of the most effective and foundational nonpharmacological approaches. Strength-based training programs have been shown to improve muscle mass and strength, reduce functional decline, and lower the risk of falls. However, despite the growing recognition of sarcopenia as a major health issue, particularly among aging populations, no drug has yet been approved by the US Food and Drug Administration as a specific treatment for this condition, due to its complex pathophysiology. This review aims to systematically summarize the epidemiological characteristics and pathogenesis of aging-, obesity-, and diabetes-related sarcopenia and to discuss evidence-based intervention strategies. Future research should focus on elucidating the underlying biological mechanisms, identifying biomarkers for early diagnosis, and developing individualized precision treatment systems.

Introduction

Sarcopenia is a syndrome characterized by a progressive decline in skeletal muscle mass and overall muscle function, including strength and performance. It is particularly common among older adults, with community-based data indicating that its prevalence can reach up to 29% in this population.^[1] Consequently, sarcopenia has become an important public health concern. The European Working Group on Sarcopenia in Older Persons (EWGSOP) defined sarcopenia as a syndrome marked by the age-related progressive loss of skeletal muscle mass, strength, and function.^[2] The implications of sarcopenia extend beyond a simple age-related condition, as it has emerged as a major clinical syndrome with serious public health consequences.^[2] It not only significantly increases the risk of falls, fractures, and physical disability but also profoundly impairs patients’ quality of life, imposing a substantial socioeconomic burden.

The incidence of sarcopenia is rapidly increasing among the three prevalent conditions—natural aging, obesity, and diabetes—due to its complex and interrelated pathology. Aging-related muscle loss results from a combination of intrinsic anabolic imbalance, neuromuscular degeneration, reduced satellite cell function, and chronic inflammation. Obesity, particularly the excessive accumulation of visceral fat, contributes to the onset and progression of sarcopenia by aggravating chronic low-grade inflammation, inducing insulin resistance, promoting lipotoxicity and muscle cell damage, and potentially reducing physical activity. These factors collectively lead to the highly detrimental phenotype known as sarcopenic obesity (SO).^[3,4] Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia and insulin resistance, with systemic complications largely mediated by chronic low-grade inflammation. Persistent metabolic stress induces the sustained elevation of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP), establishing a systemic proinflammatory milieu. This inflammatory state not only accelerates β-cell dysfunction but also directly impairs vascular endothelial integrity, promotes atherogenesis, and disrupts skeletal muscle homeostasis by regulating protein synthesis and degradation, thereby contributing substantially to the loss of muscle mass and strength.^[5,6] In addition, glucotoxicity from hyperglycemia, accumulation of advanced glycation end products (AGEs), muscle hypoperfusion due to microangiopathy, and motor unit damage from diabetic neuropathy collectively establish a vicious cycle that accelerates the loss of muscle mass and function.^[7] When aging, obesity, and diabetes coexist or even overlap in two, their pathological effects are not merely additive. Instead, they interact synergistically through inflammatory pathway activation, suppression of insulin/ insulin-like growth factor-1 (IGF-1) signaling, mitochondrial dysfunction, and excessive reactive oxygen species (ROS) production, resulting in earlier onset, faster progression, and diminished responsiveness to conventional interventions. Physical inactivity is considered the primary risk factor; individuals with sedentary lifestyles begin to experience gradual declines in muscle fibers and strength as early as 50 years of age. By the age of 80 years, the number of fibers in limb muscles, such as the vastus lateralis, decreases by approximately 50%, primarily due to the loss of type II (fast-twitch) fibers.^[8]

Given the complex coexistence of sarcopenia with these pathological conditions, a detailed analysis of their interactions, along with the development of integrated nutritional optimization strategies, is essential. Comprehensive intervention approaches—such as adequate intake of high-quality protein and vitamin D, combined resistance and aerobic exercise, correction of metabolic disorders, precise regulation of blood glucose and lipid levels, and emerging anti-inflammatory or anabolic drugs (including myostatin inhibitors and selective androgen receptor modulators)—possess not only significant scientific value but also urgent clinical relevance for improving, patient outcomes and quality of life. This review systematically examines the unique pathophysiological network underlying sarcopenia in the contexts of aging, obesity, and diabetes. It further highlights current and emerging preventive strategies to provide a theoretical foundation and practical direction for addressing the major challenges in this multifactorial field.

Diagnosis Criteria of Sarcopenia

Sarcopenia is clearly defined as a muscle disease resulting from the accumulation of adverse changes in muscle throughout the life course, affecting not only in older adults but also individuals at earlier ages. In 2010, the EWGSOP proposed the diagnostic criteria for sarcopenia, which required both low muscle mass and either low muscle strength or low physical performance. In 2018, EWGSOP2 updated these criteria to emphasize low muscle strength—currently regarded as the most reliable indicator of muscle function—as the principal feature of sarcopenia. The diagnosis is confirmed by evidence of low muscle quantity and quality, while poor physical performance serves as an indicator of severe sarcopenia. In the revised guidelines, muscle strength is considered a more effective predictor of poor outcomes than muscle quality.^[9] The detection algorithms for sarcopenia are based on assessments of gait speed, handgrip strength, and muscle mass measurements^[10–17] [Table 1]. According to European diagnostic cutoffs, low muscle mass is defined as a skeletal muscle mass index below 7.0 kg/m² for men and less than 5.5 kg/m² for women; low muscle strength is defined as handgrip strength below 27 kg for men and below 16 kg for women. Low physical performance is defined as a gait speed of below 0.8 m/s. Low muscle strength indicates probable sarcopenia, which is confirmed when reduced muscle mass or quantity is also present. Severe sarcopenia is diagnosed when decreased handgrip strength and/or gait speed are accompanied by a substantial reduction in skeletal muscle mass.^[8,18] Due to racial and ethnic variability, diagnostic criteria and thresholds differ between European and Asian populations. The current diagnostic criteria (low muscle mass <7.0 kg/m² for men and less than 5.7 kg/m² for women detected by biological impedance analysis; handgrip strength <28 kg for men and <18 kg for women; 6-m gait speed <1.0 m/s) for sarcopenia in Asian populations were updated by the Asian Working Group for Sarcopenia in 2019.^[19] For the intervention and management of sarcopenia among Asian populations, timely application of the Asian Working Group for Sarcopenia 2019 criteria for early screening and diagnosis is essential, particularly for high-risk groups such as older adults, individuals with obesity, and patients with diabetes.

Table 1.

The detection algorithms for muscle mass, muscle strength, and physical performance.

Muscle mass detection	Features	References
CT	Advantage: accurate Disadvantage: radiation exposure, limited access	[10]
MRI	Advantage: accurate Disadvantage: high cost, limited access	[11]
DXA	Advantage: full-body scan, minimal radiation Disadvantage: not portable	[12][123]
BIA	Advantage: inexpensive, easy to use, easy to repeat, suitable for ambulatory and bedridden patients Disadvantage: accuracy limitation	[9][10][11]
Muscle strength assessment
Handgrip strength	Measured by a grip dynamometer, inexpensive, rapid, simple	[13][14][15]
In a standing position	Reflect the lower body and core muscle strength	[13]
In a sitting position	Reflect the strength of smaller muscle groups in the wrist and the upper body	[14]
Physical performance assessment
Gait speed (4- or 6-m walking gaint speed)	Simple to perform, requiring only minimal space and a timer	[16][17][19]
Five-time chair stand test	Easy to perform in a variety of settings using only a timer and a chair	[19]
Time-up and go test	Perform with a standard armchair and a timer	[9]
Short physical performance battery	Includes three different domains: walking, sit-to-stand, and balance	[9] [19]
400 m walk test	Requires a spacious area	[9]

BIA: Biological impedance analysis; CT: Computed tomography; DXA: Dual-energy X-ray absorptiometry; MRI: Magnetic resonance imaging.

Aging-Related Sarcopenia

Vitality represents the fundamental physiological foundation of frailty, with neuromuscular functions—such as grip strength, knee extensor strength, and respiratory muscle strength—identified as key determinants of vitality.^[20] The decline in vitality is considered a precursor to frailty. Frailty refers to a state in which the body’s functional reserves are reduced, leading to increased vulnerability to adverse health events. Sarcopenia, in contrast, is characterized by a progressive decline in skeletal muscle mass and function and represents a central pathological basis of physical weakness. In aging populations, frailty and sarcopenia markedly reduce healthy life expectancy. The prevalence of frailty ranges from 50% to 75%, and that of sarcopenia from 19.5% to 47.3%, with a 1.5- to 3-fold increase in 1-year mortality.^[21] These conditions further elevate the risk of falls, fractures, and even death. With advancing age, detrimental alterations occur in skeletal muscle, including muscle atrophy, transition of fast-twitch fibers to slow-twitch fibers, increased collagen deposition, and reductions in both muscle fiber number and function, ultimately leading to sarcopenia.^[22] Human skeletal muscle atrophy associated with aging exhibits muscle-specific patterns, with different muscle groups showing distinct rates of decline. Among these, the rectus femoris demonstrates the most pronounced atrophy between the ages of 25 and 75 years.^[23] Age-related sarcopenia is classified as primary sarcopenia, whereas sarcopenia resulting from chronic diseases or other pathological conditions is classified as secondary sarcopenia.^[24] Under severe conditions, muscle mass may decline by approximately 50% by the eighth to ninth decades of life.^[25] Cellular senescence is characterized by a metabolically active state, shortened telomeres, elevated ROS, persistent DNA damage, altered gene expression, and secretion of inflammatory molecules such as Interleukin (IL)-1α, IL-6, and IL-8—partially regulated by nuclear factor kappa B (NF-κB)—resulting in a senescence-associated secretory phenotype.^[26] Senescent cells cumulatively release proinflammatory cytokines that aggravate tissue inflammation and functional deterioration.^[27] In addition to chronic inflammation and impaired protein turnover in the elderly, mitochondrial dysfunction and degeneration of neuromuscular junctions (NMJs) cause muscle cell damage that further accelerates the progression of sarcopenia.

Turnover imbalance of protein

The atrophy or hypertrophy of muscle fibers depends on their protein content, as more than 80% of muscle dry weight consists of protein.^[25] In older adults, higher protein doses ( ≥20 g per meal) are required to maximally stimulate muscle protein synthesis, whereas in young adults, protein intakes exceeding this threshold (>20 g per meal) primarily lead to increased amino acid oxidation without additional anabolic benefits.^[28] Theoretically, muscle hypertrophy occurs when protein synthesis increases, and degradation is suppressed, whereas muscle atrophy develops when degradation exceeds synthesis. Age-related deterioration of skeletal muscle structure and function—manifested as reduced muscle strength, contractility, and endurance—is primarily attributed to imbalances in muscle protein synthesis and degradation. Studies have demonstrated that muscle atrophy-related factors increase in the skeletal muscle of elderly humans and aging rats.^[29] Muscle protein synthesis declines with age, and even when circulating amino acid levels are comparable, older adults exhibit impaired muscle anabolism—a phenomenon known as “anabolic resistance”.^[30] The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway acts as a downstream effector of protein kinase B (AKT), a central receptor of cell growth and nutrient status, and serves as a key regulator of protein metabolism.^[31] mTORC1 modulates protein synthesis and degradation by integrating multiple intracellular signals. For example, leucine functions not only as a building block for muscle protein synthesis but also as a signaling molecule that directly stimulates protein synthesis by activating mTORC1 in muscle cells.^[32] Due to the reduced sensitivity of mTORC1 to leucine, age-related skeletal muscle mass loss is unlikely to be improved by dietary protein intake in older individuals.^[33] Research indicated that mTORC1 enhanced protein synthesis by phosphorylating the eukaryotic initiation factor 4E-binding protein 1 and p70 ribosomal S6 kinase 1 (S6K1).^[34] Moreover, activation of S6K1 by mTORC1 enhances messenger RNA biogenesis, cap-dependent translation initiation, translational elongation, and the synthesis of ribosomal proteins. These effects are mediated through the regulation of multiple downstream targets, including S6K1 Aly/REF export factor-like target, programmed cell death protein 4, eukaryotic elongation factor 2 kinase, and ribosomal protein S6.^[34,35] However, decreased mTORC1 responsiveness to amino acids, such as leucine in older individuals disrupts the balance between protein synthesis and degradation, thereby promoting the progression of sarcopenia.

Chronic inflammation

Infections, mechanical stress, chemical agents, and extreme temperatures can damage tissues and trigger nonspecific inflammatory responses. Because progressive tissue destruction poses a threat to organismal survival, inflammation functions as a protective mechanism that initiates tissue repair. Without inflammation, wounds and infections would fail to heal. In healthy organisms, where the purpose of inflammation is to clear damaged cells and begin tissue regeneration, systemic inflammation remains a tightly regulated process essential for survival.^[36] Aging can be understood as a gradual imbalance between the random accumulation of cellular damage and the reparative mechanisms that continually counteract this damage, ultimately leading to chronic diseases, frailty, and mortality. Indeed, aging is associated with persistent immune activation, reflected by elevated circulating levels of inflammatory markers and activation of immune cells in both circulation and tissues.^[37] Triggering receptor expressed on myeloid cells 2-positive macrophages are specifically enriched in the skeletal muscle and bone of older adults. This macrophage subset is highly expressed to promote fibrosis and acts as a key effector population mediating muscle atrophy and bone loss.^[38] Inflammation during aging is characterized by an upregulation of immune and inflammatory responses, a state commonly referred to as “inflammaging”. The age-related chronic low-grade inflammatory profile has been recognized as an important etiological factor in the development of sarcopenia.^[39] As aging impairs immune function, older adults become more susceptible to chronic inflammation—a persistent, mild inflammatory state. This condition is characterized by slightly elevated blood concentrations of proinflammatory cytokines, including TNF-α, IL-6, and IL-18. C-reactive protein, an acute-phase protein synthesized by the liver in response to IL-6, is also upregulated during chronic inflammation. Blood levels of TNF-α, IL-1β, and IL-6 are approximately two- to four-fold higher in older adults than in healthy younger individuals.^[40] The major inflammatory mediators involved in this process include TNF-α, IL-6, IL-1, and chemokines, which promote inflammatory cell infiltration through activation of the NF-κB signaling pathway, thereby contributing to muscle degeneration.^[41]

Mitochondrial disorders

Mitochondria, as central organelles within cells, perform multiple critical physiological functions, including adenosine triphosphate synthesis, metabolic regulation, ROS generation, maintenance of intracellular calcium homeostasis, and regulation of apoptosis.^[42] Under hypoxic conditions, the basal and maximal mitochondrial oxygen consumption rates of aged myoblast precursor cells are comparable to those of young myoblast precursor cells. However, under normoxic conditions, both basal and maximal mitochondrial oxygen consumption rates in aged myoblast precursor cells are significantly lower than those in the young group,^[43] indicating that mitochondria in aged muscle are more susceptible to oxidative stress, leading to reduced mitochondrial function. In aged muscle, the release of proapoptotic factors such as cytochrome c and apoptosis-inducing factor increases, activating the mitochondrial apoptotic pathway and inducing nuclear loss or myofibrillar degradation through caspase-dependent and caspase-independent mechanisms.^[44] Pyruvate dehydrogenase kinase 4 regulates cellular energy metabolism by phosphorylating and inhibiting the pyruvate dehydrogenase complex, thereby limiting pyruvate oxidation in the tricarboxylic acid cycle. Pyruvate dehydrogenase kinase 4 is upregulated during muscle atrophy and is closely associated with mitochondrial dysfunction, increased proteolysis, and abnormal myogenesis. Its core mechanism involves disruption of mitochondria-associated membranes and mitochondrial quality control, contributing to the pathogenesis of metabolic disease-associated muscle atrophy.^[45] Mitochondria are not only cellular energy factories but also central regulators of muscle mass. Their dysfunction forms the pathological basis of muscle aging and atrophy through interconnected mechanisms of oxidative stress, apoptotic signaling activation, metabolic remodeling, and failure of the quality control system, thereby providing key targets for therapeutic intervention.

Satellite cell function decline

Skeletal muscle is an organ highly susceptible to damage from overload and trauma; however, it possesses remarkable regenerative capacity. Muscle fibers are generally categorized into fast- and slow-twitch fibers. These fibers are multinucleated cells formed through the fusion of satellite cells.^[46] Satellite cells, which are skeletal muscle-specific stem cells, play a central role in muscle regeneration.^[47] Under normal conditions, they remain in a quiescent state;^[48] however, when nearby muscle fibers are damaged, they become activated in response to injury signals and differentiate into muscle progenitor cells.^[49] These progenitor cells proliferate and fuse with each other or with existing muscle fibers, contributing to the formation, repair, and hypertrophy of new fibers. During aging, the number of satellite cells in fast-twitch fibers decreases markedly, leading to impaired regenerative capacity, whereas satellite cells in extraocular and masticatory muscles exhibit higher density and sustained regenerative potential.^[50] The overall decline in satellite cell number with advancing age is closely associated with reduced muscle regeneration capacity.^[51] Reduced expression and activation of dynamin-related protein 1 in aged satellite cells lead to phenotypes characterized by abnormal mitochondrial networks, impaired oxidative phosphorylation, and decreased autophagy.^[52] Muscle regeneration is maintained through macrophage infiltration and the subsequent secretion of anti-inflammatory cytokines that promote satellite cell activation and protein synthesis.^[53] Aging also impairs the self-renewal capacity of satellite cells. The Notch signaling ligand plays essential roles in satellite cell activation, proliferation, and self-renewal; however, its activity declines in senescent cells,^[54] resulting in impaired functional expression of satellite cells. Concurrently, the Janus kinase (JAK) /signal transducer and activator of transcription (STAT) signaling pathway becomes overactivated in senescent cells, driving asymmetric satellite cell division and thereby reducing their self-renewal capacity and depleting the stem cell pool. Targeted inhibition of the JAK/STAT pathway can significantly enhance muscle regeneration and functional recovery in older adults,^[55] offering a promising therapeutic strategy for muscle atrophy-related disorders.

Degeneration of NMJs

NMJs are critical synaptic interfaces that mediate neural control of muscle activity and exhibit high structural and functional plasticity. Variations in motor unit size, activity patterns, and muscle fiber properties profoundly influence the physiological characteristics and pathological vulnerability of NMJs.^[56] Studies of single muscle fiber mechanics have demonstrated the intrinsic mechanisms underlying age-related muscle impairment: diminished active contractile function combined with increased passive stiffness contributes to muscle hypotonia.^[57] As the integrative hub between the nervous and muscular systems, the structural and functional integrity of the degeneration of NMJ directly determines muscle force generation, highlighting that postsynaptic alterations—such as junctional fold simplification and voltage-gated sodium channel or chloride channel dysfunction—are primary contributors to functional decline.^[58] It has been reported that NMJs in the diaphragm of middle-aged mice compensate for the reduction in postsynaptic receptor function through enhanced presynaptic neurotransmitter release and accelerated neural conduction.^[59] This adaptive mechanism may increase diaphragmatic contractility and modulate respiratory patterns, serving as an early compensatory response preceding NMJ degeneration and age-related diaphragmatic atrophy. In senescence-sensitive muscles, such as the tibialis anterior, extensor digitorum longus, and soleus, the increased number and altered spatial distribution of perisynaptic Schwann cells contribute directly to age-associated NMJ degeneration.^[60] In aged mouse models, H₂O₂ generated by muscle mitochondria acts as a central effector mediating NMJ damage, leading to muscle atrophy and progressive loss of muscle function.^[61] Thus, the combined effects of these biological factors contribute to NMJ deterioration and promote the development of sarcopenia.

Decreased activity leads to muscle loss

Age-related loss of skeletal muscle mass results from both a reduction in the number of muscle fibers and atrophy of individual fibers. Disuse-induced muscle atrophy, such as that caused by prolonged bed rest or physical inactivity, also contributes to secondary sarcopenia, primarily through a decrease in muscle fiber cross-sectional area.^[24] Extended periods of inactivity lead to mitochondrial dysfunction and disruption of neuromuscular connections. However, secondary sarcopenia resulting from disuse atrophy can often be substantially improved through endurance exercise and appropriate nutritional supplementation.

Obesity-Related Sarcopenia

Obesity is defined as an abnormal or excessive accumulation of body fat that adversely affects health.^[62] The body mass index (BMI) cut-off point used to define obesity originates from studies examining the relationship between BMI and mortality, which identified a sharp increase in all-cause mortality at values exceeding 30 kg/m². Obesity represents a major global health threat and a significant risk factor for metabolic and cardiovascular morbidity and mortality.^[63] This section focuses on the impact of fat accumulation on the development of sarcopenia. Elevated triglyceride levels may serve as a risk factor associated with sarcopenia, often linked to conditions such as obesity, insulin resistance, and dyslipidemia; therefore, lipid control may help reduce sarcopenia risk.^[64] Age-related muscle mass loss is often counterbalanced by an increase in fat mass. Consequently, body weight in men and women may remain relatively stable or even increase slightly during middle age, despite a rise in body fat percentage relative to lean tissue—an important step in the progression toward SO. In 2000, Baumgartner and colleagues^[65] were the first to describe SO as a phenotype characterized by the coexistence of sarcopenia and obesity. Although BMI may remain relatively stable with age, significant age-related changes in body composition occur, including an increase in fat mass and a decrease in skeletal muscle mass.^[4] Consequently, SO affects approximately 11% of the global elderly population, with its prevalence increasing markedly after the age of 70 years. It is closely associated with disability, mortality risk, and metabolic disorders.^[66] The etiology of SO is multifactorial, involving both age-related physiological changes and alterations in body composition, and is closely linked to mitochondrial dysfunction within skeletal muscle. SO has also emerged as a significant cardiovascular risk factor, particularly in older adults. SO and cardiovascular disease (CVD) share common pathophysiological mechanisms, including imbalances between proinflammatory adipokines and anti-inflammatory myokines, endothelial dysfunction, and hypertension. These abnormalities contribute to vascular remodeling and increased risk of cardiovascular events, whereas chronic CVD—such as heart failure—can further accelerate muscle wasting.^[67] Low muscle mass is an independent risk factor of both all-cause and CVD-related mortality, with the greatest risk observed in individuals with metabolic abnormalities or central obesity. Even among those with a relatively low prevalence of metabolic disorders, the direct pathological effects of low muscle mass significantly increase mortality risk.^[68]

Fat infiltration

Both primary and secondary sarcopenia are associated with alterations in lipid metabolism. Under conditions of hypernutrition, chronic stress, or prolonged physical inactivity, maladaptive expansion of adipose tissue leads to increased cellular hypoxia as adipocytes enlarge.^[69] Adipose tissue hypoxia either upregulates the expression of profibrotic genes, resulting in fat fibrosis, or directly induces adipocyte necrosis, which subsequently triggers immune cell infiltration and adipose inflammation.^[70] Because obese individuals have a higher proportion of visceral adipose tissue and a greater number of adipocytes that secrete large quantities of inflammatory cytokines, their skeletal muscle remains in a state of persistent inflammation, thereby increasing the risk of muscle atrophy.^[71] Crosstalk may also occur between muscle and fat, whereby contracting skeletal muscle releases myokines that exert endocrine effects on visceral adipose tissue.^[72] Short-term cold exposure alters the fatty acid composition of fat-infiltrated muscle by directly modulating lipid metabolism pathways, including the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase signaling pathways.^[73] Recent studies have shown that extended synaptotagmin-1 is significantly overexpressed in patients with SO and in aged skeletal muscle, where its expression is positively correlated with intramuscular adipose tissue accumulation.^[74] Silencing extended synaptotagmin-1 restores mitochondrial homeostasis and promotes muscle remodeling, representing a potential therapeutic target for SO.

Metabolic disorders

Muscle loss that exceeds normal age-related decline is closely associated with obesity and is further aggravated by complex metabolic interactions. Physiological regeneration and proliferation of muscle tissue depend on a coordinated regulation of inflammation, autophagy, satellite cell proliferation, and signaling molecule activity. Adipokines and myokines, which are signaling molecules secreted by adipose tissue and skeletal muscle, respectively, exert autocrine, paracrine, and endocrine effects on both tissues. These molecules interact to maintain metabolic homeostasis. However, excessive fat accumulation establishes a proinflammatory state that disrupts metabolic balance and leads to systemic homeostatic dysregulation.^[75] Myostatin serves as a key negative regulator of skeletal muscle mass and growth, influencing molecular pathways involved in muscle atrophy and hypertrophy. It is strongly associated with muscle wasting and fat accumulation observed in obesity, aging, and chronic diseases.^[76] Recent studies have demonstrated that serum myostatin, regulated by brown adipose tissue, inhibits the mammalian target of rapamycin (mTOR) signaling pathway and ribosomal protein synthesis in skeletal muscle. This inhibition leads to reduced mitochondrial function and impaired muscle performance.^[77] In obesity, brown adipose tissue activity is typically suppressed, resulting in elevated circulating myostatin levels and consequent motor dysfunction. The latest research confirms that sarcosine promotes muscle stem cell (MuSC) proliferation and induces the browning of subcutaneous white adipose tissue by driving macrophage polarization toward an anti-inflammatory M2 phenotype.^[78] Hormonal imbalances and excessive accumulation of ROS accelerate muscle catabolism, whereas muscle loss further reduces the basal metabolic rate, promotes fat accumulation, and perpetuates a vicious cycle of disrupted energy metabolism.^[79] Estrogen mitigates visceral fat accumulation, and testosterone enhances muscle regeneration; both exert their effects by modulating skeletal muscle inflammation and activating satellite cells.^[72] Leptin upregulates the proinflammatory cytokines IL-6 and TNF-α, which in turn suppress adiponectin expression, leading to decreased muscle fatty acid oxidation, reduced protein synthesis, and impaired mitochondrial function.^[80] Obesity further exacerbates mitochondrial dysfunction and impairs mitochondrial quality control, particularly in the clearance of damaged mitochondria.^[81] Because mitochondria are the primary source of muscle energy, obese individuals exhibit metabolic inflexibility, characterized by reduced fat oxidation during fasting, insufficient glucose oxidation after feeding, and markedly decreased glucose uptake and oxidative capacity in myotubes.^[82]

Diabetes-Related Sarcopenia

The global prevalence of diabetes is projected to rise exponentially in the coming decades, with older adults (aged >65 years) bearing the greatest burden. Up to 70% of adults with diabetes experience difficulty performing daily physical tasks, particularly those involving lower extremity mobility, and diabetes remains a major risk factor for multiple geriatric syndromes.^[83] Diabetes accelerates age-related declines in muscle mass and strength, impairs balance and increases the risk of falls, and, when coexisting with sarcopenia exacerbate muscle loss, uncontrolled blood sugar, and reduced quality of life.^[84,85] Studies have demonstrated that older adults with T2DM exhibit a significantly increased prevalence of sarcopenia compared with non-diabetic individuals over 50 years of age (27.9% vs. 15.7%).^[86] T2DM is characterized by chronic inflammation, insulin resistance, accumulation of AGEs, and oxidative stress.^[87] Skeletal muscle serves as the primary site of insulin-stimulated glucose uptake and metabolism.^[88] In older adults, T2DM is associated with accelerated loss of leg muscle mass and strength.^[89] T2DM-associated sarcopenia represents a crucial link between diabetic pathology and increased susceptibility to falls and fractures, not only heightening the risk of accidental falls but also perpetuating a vicious cycle of impaired musculoskeletal health that further amplifies fracture risk. Specifically, older adults with sarcopenia have been shown to have more than double the risk of experiencing falls (adjusted hazard ratio: 2.38, corresponding to a ~138% increase) compared with those without sarcopenia, and older adults with T2DM more broadly have been reported to have a ~49% higher chance of falls compared with non-diabetic peers.^[90]

Insulin resistance

Insulin resistance is defined as a reduced response to insulin-stimulated glucose uptake and utilization.^[91] It represents a central pathological feature of metabolic disease; however, its clinical assessment remains complex. Sarcopenia, characterized by progressive muscle loss in aging, and insulin resistance are interrelated conditions commonly associated with metabolic dysfunction.^[92] Elevated levels of proinflammatory cytokines frequently observed in patients with T2DM—including TNF-α, IL-1, IL-5, and IL-6—can induce or aggravate insulin resistance.^[93] Additionally, elderly participants exhibited pronounced insulin resistance compared with young controls, which was associated with increased intramuscular and hepatic fat accumulation and an approximately 40% reduction in mitochondrial oxidative and phosphorylation capacity, supporting a contributory role of mitochondrial dysfunction in the development of insulin resistance.^[94] Evidence from genetic and epidemiological studies indicates that each 1-standard deviation (SD) decrease in appendicular lean mass is causally associated with a higher risk of diabetes (odds ratio [OR]: 1.20). Mediation analyses further suggest that insulin resistance accounts for approximately 7–28% of the effect of reduced appendicular lean mass on diabetes risk, supporting the concept that muscle loss contributes to impaired insulin sensitivity and, consequently, the development of systemic insulin resistance.^[95] In addition, insulin resistance reduces activation of protein synthesis pathways and enhances protein degradation, ultimately resulting in muscle loss in T2DM.^[96] Apart from insulin resistance, elevated nocturnal cortisol levels and flattening of circadian rhythms are common in patients with T2DM. Excess cortisol promotes protein catabolism and inhibits protein synthesis, leading to reduced muscle mass and strength and contributing to sarcopenia.^[97] Because of these interconnected mechanisms, sarcopenia, and obesity frequently coexist with diabetes. Compared with non-diabetic individuals, patients with diabetes exhibit decreased lean body mass alongside increased fat mass.^[98] Aging and obesity act as shared risk factors, establishing a bidirectional vicious cycle in which diabetes induces insulin resistance and muscle degradation, while SO further aggravates insulin resistance and metabolic disturbances.^[99] Under diabetic conditions, excessive fat deposition within skeletal muscle and epicardial tissue exacerbates insulin resistance,^[100] further impairing glucose utilization and muscle function.

Accumulation of AGEs

AGEs are formed through the nonenzymatic glycosylation of macromolecules such as proteins and lipids.^[7] As terminal products of late-stage glycation, plasma pentosidine and other AGEs are associated with sarcopenia, reduced walking speed, and increased mortality. AGEs accumulate in tissues by inducing oxidative stress, stimulating inflammation, and inhibiting the insulin-like growth factor-1 signaling pathway, thereby exacerbating muscle loss and functional decline.^[101] Similarly, AGEs are overproduced and accumulated in patients with chronic kidney disease, oxidative stress, and inflammation that impair muscle nutrition and function, ultimately contributing to the onset of sarcopenia.^[102] In aging skeletal muscle, AGEs accumulate on collagen fibers through the nonenzymatic Maillard reaction.^[103] Because collagen has a long half-life and is rich in lysine and arginine residues, it serves as a primary target for AGE modification. AGEs promote nonenzymatic crosslinking reactions,^[104] resulting in collagen sclerosis, extracellular matrix (ECM) remodeling, and muscle-type specific alterations that impair contractile function. Furthermore, AGEs activate adenosine 5′-monophosphate-activated protein kinase (AMPK) via the receptor for AGEs, subsequently inhibiting the AKT pathway and upregulating atrogin-1 expression, which together lead to muscle fiber atrophy and degeneration.^[105]

Diabetes-related cardiovascular disease

Diabetes is frequently accompanied by macrovascular complications, such as atherosclerosis and coronary heart disease, as well as microvascular complications, including diabetic nephropathy and diabetic retinopathy. T2DM is often associated with obesity, and alterations in visceral fat distribution and skeletal muscle mass are recognized as major determinants of cardiometabolic disease risk, particularly among individuals with T2DM. In obese patients with sarcopenia, both carotid intima-media thickness and cardiovascular mortality are markedly increased.^[106] The skeletal muscle mass to visceral fat area ratio is negatively correlated with the 10-year risk of CVD in patients with T2DM;^[107] lower skeletal muscle mass to visceral fat area ratio values are associated with a higher 10-year CVD risk and a greater likelihood of developing sarcopenia. The appendicular skeletal muscle mass index, a key diagnostic indicator of sarcopenia, and the estimated glucose disposal rate, a surrogate marker of insulin resistance, are both strongly associated with CVD.^[108] Insulin resistance inhibits the PI3K/AKT signaling pathway, leading to vascular endothelial dysfunction, while simultaneously activating the MAPK pathway to promote vascular smooth muscle proliferation, inflammation, and atherosclerosis. Skeletal muscle deficiency and T2DM form a self-perpetuating vicious cycle through insulin resistance, chronic inflammation, oxidative stress, and the accumulation of AGEs, which together exacerbate both macrovascular and microvascular complications.^[109]

Diabetic neuropathy

Diabetic neuropathy is a prevalent chronic complication of T2DM that primarily affects the peripheral nervous system, leading to impairments in motor, sensory, and autonomic nerve function.^[110] Diabetic peripheral neuropathy (DPN) serves as a major risk factor for sarcopenia and physical debilitation in older adults with diabetes.^[111] The presence of diabetic neuropathy has been associated with reduced walking speed and diminished grip strength, and the frequency of gait impairment increases in proportion to the severity of DPN.^[112] Among individuals with T2DM, the prevalence of DPN is significantly higher in those with sarcopenia than in those without (80.0% vs. 70.3%), moreover, DPN is an independent risk factor for sarcopenia in individuals with T2DM (OR: 1.564), with greater neurological symptom severity corresponding to a more pronounced reduction in skeletal muscle mass.^[113] Motor neurons and the muscle fibers they innervate collectively form motor units, which naturally decline with aging; under diabetic conditions, this decline accelerates, contributing to both neuropathy and sarcopenia.^[114] Neuropathy induces muscle denervation through motor axon loss, resulting in progressive muscle atrophy and decreased strength.

Synergy

Inflammation represents an innate defense mechanism that initiates tissue repair in response to damage caused by infection, mechanical stress, chemical exposure, or extreme temperatures. Sarcopenia is primarily driven by physical inactivity and systemic inflammation, both of which decrease protein synthesis while enhancing protein degradation. This imbalance results in the progressive loss of muscle mass and function frequently observed in aging and various chronic diseases. Inflammation is not only associated with aging but is also strongly linked to SO, as evidenced by disturbances in glucose metabolism, insulin resistance, oxidative stress, and elevated production of inflammatory cytokines.^[115] In particular, inflammation within adipose tissue serves as a critical trigger and driver of skeletal muscle degeneration.^[116] Elevated lipid levels and higher BMI contribute to a self-reinforcing cycle of intramuscular fat infiltration, inflammation, oxidative stress, and insulin resistance, all of which impair muscle integrity during aging.^[117] In individuals with obesity or T2DM, skeletal muscle mitochondria are smaller and exhibit poorly defined inner membranes containing vacuoles; mitochondrial size correlates inversely with glucose disposal rate and insulin sensitivity.^[118] Chronic inflammation further induces mitochondrial dysfunction and disrupts neuromuscular connectivity.^[119] Additionally, age-related gut microbiota dysbiosis contributes to inflammation, insulin resistance, muscle atrophy, and fat accumulation, forming a key mechanistic link in SO pathogenesis. Normal gut–muscle interactions are essential for optimal protein utilization, amino acid absorption, and detoxification of harmful metabolites.^[120] At the core of the coexistence of age-related obesity and muscle loss lies a vicious cycle of chronic inflammation, sustained by the interplay among skeletal muscle, lipid toxicity, and inflammatory signaling.

Intervention and Treatment of Sarcopenia

Despite substantial progress in understanding sarcopenia and its complications, there remains no definitive cure for age-related or disease-associated muscle loss.^[121] Exercise is well recognized for its role in maintaining muscle mass and strength; however, it may not directly influence or affect the underlying biological mechanisms driving sarcopenia. Thus, determining the most effective therapeutic strategy for managing this condition remains an open and evolving question.^[96] The 2018 international consensus guidelines on sarcopenia strongly recommend resistance-based exercise training and conditionally recommend increasing total protein and caloric intake, including the use of protein supplementation when necessary.^[122] In the coming decades, advances are expected in the integration of routine health data, development of personalized resistance exercise prescriptions, and translation of biological and epidemiological findings into first-in-human therapeutic studies, with greater emphasis on sarcopenia prevention and treatment in low- and middle-income countries.^[123] Older adults aged 65 years and above should undergo annual sarcopenia screening or be re-evaluated following major health events. Regular screening serves as an effective approach for early detection and intervention in sarcopenia progression. First, all older adults are at risk for sarcopenia, particularly those with low levels of physical activity.^[124] Second, sarcopenia is prevalent among aging populations and may initially present as a transient condition. Third, sarcopenia imposes a considerable burden on affected individuals, caregivers, and healthcare systems. Fourth, early screening and timely intervention substantially improve management outcomes. Optimizing metabolic health and weight control in older adults, while maintaining adequate but not excessive fat stores, may represent an important strategy to prevent or delay sarcopenia onset. In recent years, accumulating evidence has identified several preventive measures and interventions with potential efficacy against sarcopenia [Figure 1].

Figure 1.

Potential interventions for sarcopenia.

Nondrug therapy

Resistance exercise

Studies have demonstrated that combined exercise programs provide greater benefits in weight reduction, fat loss, and cardiorespiratory fitness than either aerobic or resistance training alone. Therefore, combined training should be incorporated into national physical activity guidelines^[125] for overweight and obese adults. A properly structured resistance training program, accompanied by appropriate instruction and safety measures, is essential for older adults to reduce fall risk and enhance long-term well-being.^[126] Resistance exercise promotes muscle protein synthesis, leading to increases in muscle mass and strength. Notably, improvements in muscle strength often occur within a few days of initiating exercise—well before measurable increases in muscle mass—indicating that early benefits may stem primarily from neural adaptations rather than hypertrophy. After 12 weeks of resistance exercise, individuals with diabetes exhibited a significant reduction in hemoglobin A1c (HbA1c) levels (from 8.1 ± 1.1% to 7.7 ± 0.9%), accompanied by marked increases in grip strength (from 15.9 ± 5.0 kg to 19.1 ± 4.9 kg) and appendicular skeletal muscle mass index (from 6.9 kg/m² ± 0.9 kg to 7.1 ± 1.0 kg/m²), indicating that exercise can enhance glucose metabolism and muscle function.^[127] Furthermore, in overweight and obese patients with diabetes, combining resistance training with energy-restricted, high-protein diets produces greater weight loss and more favorable body composition changes after 16 weeks than either intervention alone. Exercise also attenuates muscle loss by inhibiting NF-κB activation and enhancing the release of myogenic IL-6.^[128] Endurance training reverses structural degeneration at the neuromuscular junction and preserves neuromuscular function, providing a mechanistic basis for its antiaging effects.^[129] Additionally, exercise induces the release of exerkines and myokines that combat sarcopenia by promoting energy redistribution, satellite cell activation, gene expression regulation, and improvement of neuromuscular signaling.^[130]

Nutritional support

Although nutrition plays a pivotal role in the management of sarcopenia, most existing evidence regarding its impact on muscle function is derived from short-term, small-sample studies, and large-scale randomized clinical trials remain limited. Currently, there is insufficient high-quality evidence to establish definitive nutritional guidelines for individuals with sarcopenia. Nevertheless, adequate intake of protein, vitamin D, antioxidant nutrients, sarcosine, and long-chain polyunsaturated fatty acids has demonstrated beneficial effects on muscle mass and function.^{[78,131–135]} A high-protein diet (1.2 g∙kg⁻¹∙day⁻¹) combined with caloric restriction significantly increases skeletal muscle mass index and reduces sarcopenia risk.^[131] Among dietary proteins, whey protein is digested and absorbed more rapidly than casein, resulting in higher plasma concentrations of essential amino acids and leucine, thereby exerting a stronger stimulatory effect on muscle protein synthesis.^[132] Leucine independently regulates protein anabolism and can counteract the anabolic resistance associated with aging muscle.^[134] Furthermore, vitamin D enhances the anabolic effects of leucine and contributes to improved muscle function.^[135] Supervised implementation of nutritional interventions is necessary to prevent injury and ensure adherence through personalized dietary counseling. In addition, sarcopenia and T2DM often exacerbate each other in older adults. This vicious cycle can be disrupted through integrated exercise and nutrition strategies, with a high-protein dietary approach as the central component.^[136]

Drug therapy

In recent years, several pharmacological approaches have been explored for the treatment of sarcopenia associated with aging, obesity, and diabetes^[137–158] [Table 2]. Maraviroc, a C-C chemokine receptor type 5 (CCR5) antagonist, has shown potential as a therapeutic agent for age-related myopenia by modulating inflammatory and senescence-related pathways. It also highlights the central regulatory role of Jun B proto-oncogene (JunB), a member of the activator protein-1 family, in mediating aging-associated secretory phenotypes,^[159] offering novel targets for antiaging interventions. Pharmacological agents such as insulin, metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and other antidiabetic drugs have been reported to reduce intramuscular lipid accumulation, thereby preserving muscle mass and delaying muscle loss.^[160] However, although hypoglycemic agents are beneficial for patients with diabetes-related sarcopenia, their potential adverse effects on overall metabolism and protein catabolism must be considered. Adequate dietary protein intake should accompany pharmacological treatment to prevent accelerated muscle loss.^[161] The fundamental pathophysiology of sarcopenia involves anabolic resistance and decreased hormone levels, both of which may be alleviated through androgen supplementation such as testosterone therapy.^[162] Since the vicious cycle of energy overload and muscle function decline represents a therapeutic bottleneck, future strategies should focus on targeting mitochondrial dysfunction, oxidative stress, and alterations in the MuSC microenvironment to improve muscle regeneration and function.^[66] Myostatin signaling is often dysregulated in sarcopenia, with elevated myostatin concentrations in both muscle tissue and plasma. This overexpression inhibits the proliferation and differentiation of MuSCs through activation of the Smad family member 2/3 (SMAD2/3) signaling cascade. Interestingly, myostatin modulation also demonstrates the potential to reverse catabolic processes under certain physiological conditions.^[163] Moreover, combined supplementation with nicotinamide and pyridoxine has been shown to synergistically activate MuSCs via dual AKT-dependent pathways, offering a safe and clinically translatable approach to promoting muscle regeneration.^[164] The interaction between bone and muscle—referred to as osteomuscular crosstalk—represents a fundamental physiological mechanism that supports musculoskeletal health across the lifespan. Age-related dysfunction in this communication accelerates the onset and progression of multiple chronic diseases.^[165] Effective treatment of sarcopenia therefore requires the integration of tri-directional signaling between bone, muscle, and adipose tissue. In developing potential pharmacological targets, it is equally important to consider adverse events related to frailty and comorbidities that may compromise treatment outcomes.^[166] Given the limited availability of large-scale clinical trials, the discovery of effective, disease-specific pharmacotherapies for sarcopenia remains an ongoing challenge.

Table 2.

Aging-, obesity-, and diabetes-related medications on each component of sarcopenia.

	Medications	Muscle mass	Muscle strength	Physical performance	Type of study	Population/model	Adverse effects	Reference
Aging	Calcium channel inhibitor thapsigargin	Increased muscle fiber cross-sectional area	Increased handgrip strength and gait speed	Accelerated recovery from muscle injuries	Preclinical study	Male mice	–	[137]
	Testosterone	Increased muscle fiber cross-sectional area	Increased handgrip strength and gait speed	Accelerated recovery from muscle injuries	Clinical trail	Older people male (aged >70 years)	–	[138]
	Vitamin D	Increased muscle fiber cross-sectional area	Increased handgrip strength and gait speed	Accelerated recovery from muscle injuries	Cohort study	Older people (aged >45 years)	–	[139]
	Nicotinamide and pyridoxine	Increased muscle fiber cross-sectional area	Increased handgrip strength and gait speed	Accelerated recovery from muscle injuries	Cohort study	Older people (aged >60 years)	–	[166]
	Polygonatum sibiricum polysaccharide	Increased muscle fiber cross-sectional area	Increased handgrip strength and gait speed	Accelerated recovery from muscle injuries	Preclinical study	Male mice	–	[182]
	Atractylenolide I	Increased muscle fiber cross-sectional area	Increased handgrip strength and gait speed	Accelerated recovery from muscle injuries	Preclinical study	Tumor-bearing mice	–	[181]
	Sarcosine	Increased muscle fiber cross-sectional area	Increased handgrip strength and gait speed	Accelerated recovery from muscle injuries	Cohort study	Sarcopenia adults	–	[78]
	Morin, Isoflavones	Increased muscle fiber cross-sectional area	–	Accelerated recovery from muscle injuries	Preclinical study	Male mice	–	[140] [183] [184]
	Buzhongyiqi decoction, Bazhen decoction	–	Increased handgrip strength and gait speed	Accelerated recovery from muscle injuries	RCT	Sarcopenia patients	–	[178] [180]
	Androgen receptor modulator	Increased lean body mass	–	–	Clinical trail	Women (aged ≥65 years)	–	[141]
	Myostatin inhibitors	Increased lean body mass	–	–	Clinical trail	Older adults (aged >75 years)/ obese adults (aged >45 years)	–	[76] [142] [171]
	Fortetropin	Increased lean body mass	–	–	RCT	Older adults (aged >65 years)	–	[143]
Obesity	Calcium channel inhibitor thapsigargin	Induces an increase in muscle-specific gravity	Improvement in muscle strength	Lean weight gain, fat loss, increased athletic ability	Preclinical study	Male mice	–	[137]
	GLP-1 receptor agonist semaglutide	Induces an increase in muscle-specific gravity	Improvement in muscle strength	Lean weight gain, fat loss, increased athletic ability	Preclinical study	T2DM mice/obese mice	Lean body mass decreased	[144] [145] [146]
	Denosumab	Induces an increase in muscle-specific gravity	Improvement in muscle strength	Lean weight gain, fat loss, increased athletic ability	Cohort study/preclinical study	Older adults (aged >75 years)/transgenic mice	Potential negative impacts exist	[147] [148]
	Statins	Induces an increase in muscle-specific gravity	Improvement in muscle strength	Lean weight gain, fat loss, increased athletic ability	Clinical trail	CKD patients	–	[149]
Diabetes	Metformin	Increased muscle mass	Improved handgrip strength, increased exercise endurance	Improved exercise speed and muscle fiber tissue structure	Preclinical study/ RCT	T2DM mice/ T2DM patients	–	[150] [151] [152]
	Galantamine	Increased muscle mass	Improved handgrip strength, increased exercise endurance	Improved exercise speed and muscle fiber tissue structure	Preclinical study	Aged mice	–	[150]
	Celecoxib	Increased muscle mass	Improved exercise speed and muscle fiber tissue structure	–	Preclinical study	Diabetic sarcopenia mice	–	[153]
	Angiotensin-converting enzyme inhibitor	Increased muscle mass	Improved exercise speed and muscle fiber tissue structure	–	Cohort study	Older adults (aged >65 years)	–	[154]
	Angiotensin II receptor blocker	Increased muscle mass	Improved exercise speed and muscle fiber tissue structure	–	RCT	HIV-infected adults	–	[155]
	SGLT2 inhibitor	–	Improved handgrip strength, increased exercise endurance	Improved exercise speed and muscle fiber tissue structure	Clinical trail	T2DM patients	–	[156] [157]
	DPP4 inhibitors	–	Improved handgrip strength, increased exercise endurance	Improved exercise speed and muscle fiber tissue structure	Clinical trail	T2DM patients	–	[158]

CKD: Chronic kidney disease; DPP4: Dipeptidyl peptidase-4; GLP-1: Glucagon-like peptide-1; HIV: Human immunodeficiency virus; RCT: Randomized Controlled Trial; SGLT2: Sodium-glucose co-transporter 2; T2DM: Type 2 diabetes mellitus; –: None/Not.

Potential targets for muscle regeneration

Targeting the myostatin signaling pathway represents a promising therapeutic strategy to enhance skeletal muscle regeneration.^[76] Both monoclonal antibodies and receptor antagonists that inhibit myostatin activity have been shown to increase muscle mass and strength in preclinical models.^[167] These pharmacological agents function by directly neutralizing myostatin, preventing its activation, or blocking receptor-mediated signaling involved in the myostatin pathway.^[168] In addition to targeting myostatin, recent research has focused on the impact of chronic inflammation on impaired MuSC function and regeneration. The ECM, together with MuSCs, constitutes a critical component of the muscle regeneration process. In mammals, the skeletal muscle ECM contributes up to 50% of total passive tension.^[169] Beyond its structural role, the ECM provides a reservoir for growth factors and signaling molecules that regulate MuSCs’ activity.^[133] Proper ECM remodeling is essential for effective muscle repair, whereas dysregulation of ECM components is associated with defective regeneration in sarcopenia.^[170] Skeletal muscle regeneration proceeds through basement membrane-guided, staged fusion of myogenic cells, with macrophage-mediated debris clearance serving as a pivotal step in the formation of linear, functional muscle fibers. Regenerative muscle fibers are distinguished from developmental muscle fibers by the presence of persistent centrally located nuclei, which serve as structural markers of pathological repair and provide a framework for understanding muscle regeneration mechanisms.^[171] Advances in gene-editing technologies, particularly the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, have introduced new possibilities for therapeutic muscle regeneration. Gene-editing approaches can be utilized to correct pathogenic mutations that impair muscle function or to enhance the expression of genes involved in muscle growth and repair. For instance, CRISPR/Cas9-mediated knockout of the myostatin gene has been shown to significantly increase muscle mass and strength in preclinical animal models.^[172] Stem cell-based therapy represents another promising avenue for promoting muscle regeneration, utilizing stem cell populations beyond MuSCs. Mesenchymal stem cells, in particular, possess the capacity to differentiate into myogenic cells and secrete paracrine factors that enhance MuSC activity and support muscle repair.^[173] Translating these advances into clinical applications holds substantial promise for developing effective treatments for sarcopenia and related muscle-degenerative disorders. Muscular dystrophy, as a high-burden yet potentially modifiable age-associated disease, underscores the need for standardized clinical protocols and the advancement of targeted therapeutic interventions aimed at improving the quality of life for affected individuals worldwide.^[174]

Traditional Chinese medicine for sarcopenia intervention

With the growing recognition of traditional Chinese medicine (TCM), increasing evidence suggests that herbal preparations and their bioactive derivatives may provide effective therapeutic options for sarcopenia management. TCM offers a range of holistic and flexible treatment modalities, including herbal therapy, acupuncture, massage, moxibustion, and traditional exercises. These approaches not only enhance muscle mass and functional capacity but also improve overall physical well-being, particularly among older adults.^[170–175] TCM-based exercises such as Qigong—including Baduanjin, Taiji, and Yijin Jing—have been shown to significantly improve muscle strength, gait stability, and balance in patients with sarcopenia, demonstrating both efficacy and safety.^[176,177] Clinical trial studies have indicated that Buzhongyiqi Decoction and Bazhen Decoction, two traditional Chinese herbal formulas, have been reported to effectively enhance muscle strength and physical performance in affected individual.^[177] Furthermore, preclinical studies in animal and cellular models have demonstrated that specific monomeric compounds from Chinese herbs, such as atractylenolide I,^[178] Polygonatum sibiricum polysaccharide,^[179] isoflavones,^[180] and morin^[181] exert protective effects against muscle atrophy, suggesting that herbal extracts enriched with these compounds may represent promising therapeutic candidates for the prevention and treatment of sarcopenia. However, their clinical efficacy warrants further validation in robust, large-scale randomized controlled trials.

Despite the increasing recognition of sarcopenia as a major global health concern, no drug has yet been approved by the U.S. Food and Drug Administration for its specific treatment. The absence of approved pharmacotherapies is largely attributed to the multifactorial nature of sarcopenia, which encompasses progressive muscle loss, nutritional deficiencies, chronic inflammation, and metabolic dysregulation. Addressing these diverse pathophysiological mechanisms through a single therapeutic agent remains a substantial challenge. Consequently, current management strategies primarily emphasize lifestyle-based interventions, including resistance exercise, increased physical activity, and dietary optimization. Ongoing research continues to investigate multiple pharmacological targets—such as hormonal modulation, anti-inflammatory agents, and myostatin inhibition—although none have yet reached clinical approval. The implementation of large-scale randomized controlled trials for those potential medicines is challenging due to multiple factors, including limited patient awareness of sarcopenia, low enrollment of eligible volunteers, substantial lifestyle-related influences on participant adherence, and unresolved concerns regarding drug safety. Thus, future investigations should therefore prioritize elucidating the underlying biological pathways, identifying reliable biomarkers for early diagnosis, and developing more effective therapeutic strategies for patients with severe sarcopenia, alongside establishing sensitive and standardized measures to predict treatment responsiveness.

Limitations

Sarcopenia associated with aging, obesity, and diabetes is a multifactorial and pathophysiologically complex condition. Its prevention and management should begin with foundational lifestyle modifications and be accompanied by active control of underlying comorbidities. Currently, due to the incomplete understanding of its molecular and physiological mechanisms, the prevention and treatment of sarcopenia continue to present major challenges. Mechanistic studies rely heavily on animal models, which limits the direct applicability of experimental findings to human populations. Furthermore, the lack of long-term, large-scale clinical trials investigating both pharmacological and TCM-based interventions restricts the ability to determine their sustained efficacy and safety. Future efforts should focus on the development of mechanism-based pharmacological therapies and integrative intervention strategies aimed at delaying muscle loss, maintaining functional capacity, and improving the quality of life in affected individuals.

Summary and Prospect

Sarcopenia is a clinical syndrome characterized by a progressive and generalized decline in skeletal muscle mass, strength, and function. It is now recognized not merely as an inevitable outcome of aging but as a multifactorial condition intricately linked with major metabolic disorders such as obesity and diabetes. These comorbidities substantially exacerbate functional impairment, metabolic dysregulation, and the risk of falls, hospitalization, and mortality, posing a significant global health burden. Under pathological conditions, aging, obesity, and diabetes synergistically accelerate the onset and progression of sarcopenia through a range of interconnected mechanisms [Figure 2]. Although muscle mass naturally declines with age, contemporary sedentary lifestyles further amplify this process. Excess adipose tissue infiltration into skeletal muscle leads to the development of a more deleterious phenotype—SO—characterized by simultaneous fat accumulation and muscle loss. Obesity-induced chronic inflammation and insulin resistance further intensify muscle protein degradation. Actually, sarcopenia, obesity, and SO are dynamic conditions that may potentially revert to a normal state in their early stages.^[182] The UK Biobank data suggested that individuals with sarcopenia exhibited a 1.73-fold higher risk of T2DM.^[183] Conversely, diabetes-associated hyperglycemia, accumulation of AGEs, diabetic neuropathy, and vascular complications collectively disrupt muscle protein homeostasis and impair neuromuscular function. In summary, the biological mechanisms underlying sarcopenia exhibit substantial heterogeneity across aging, obesity, and diabetes. Age-related sarcopenia is predominantly driven by mitochondrial dysfunction and progressive NMJ degeneration. In contrast, obesity-associated sarcopenia primarily arises from intramuscular lipid accumulation and adipokine dysregulation. Diabetes-related sarcopenia is mechanistically linked to insulin resistance-driven proteolysis and microvascular impairment.

Figure 2.

The intricate relationship between aging, obesity, and diabetes related sarcopenia. ROS: Reactive oxygen species.

Our group has long been committed to elucidating the molecular mechanisms regulating muscle regeneration and function. Over the past decade, we have systematically investigated the intrinsic regulatory networks governing muscle physiology and the contribution of skeletal muscle to systemic metabolic homeostasis. We demonstrated that Brg1/Brm-associated factor 60c (BAF60c) promotes the glycolytic conversion of skeletal muscle fibers through the Six4–Deptor–AKT signaling axis, thereby providing direct molecular evidence that glycolytic muscle fibers confer metabolic benefits and represent a viable therapeutic target.^[184] BAF60c functions as both a key regulator of systemic glucose homeostasis and a glucose sensor within skeletal muscle.^[185,186] Further studies revealed that concurrent deficiency of BAF60a and BAF60c disrupts the metabolic coordination between skeletal muscle activity and whole-body energy balance.^[187] Importantly, subsequent findings demonstrated that BAF60c in skeletal muscle represses the expression of the myokine Dickkopf Wnt signaling pathway inhibitor 3 by interacting with the transcription factor Six4, thereby enhancing MuSC regenerative potential.^[188] In addition, BAF60c inhibits the expression of the myokine Musclin by recruiting myocyte enhancer factor 2C, leading to increased adipose thermogenesis and improved whole-body metabolic homeostasis.^[189,190] Collectively, these findings provide novel insights into muscle metabolism regulation and identify potential molecular targets for sarcopenia intervention and treatment.

Sarcopenia associated with aging, obesity, and diabetes represents a multifactorial disorder driven by complex pathophysiological mechanisms. Its prevention and management should begin with fundamental lifestyle modification and the active treatment of underlying metabolic diseases, while future research should focus on developing targeted pharmacological therapies to complement comprehensive strategies aimed at delaying muscle loss and preserving functional independence and quality of life. Equally important is strengthening patient education, enhancing awareness of sarcopenia, and promoting individualized “exercise–nutrition–pharmacotherapy” programs to optimize prevention and treatment outcomes.

Acknowledgements

We thank the Gao lab members for the helpful discussion on this study. We would like to thank Editage (www.editage.cn) for English language editing.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82571830, 82300910, 82425012, and 32471170), the Joint Fund of Zhejiang Provincial Natural Science Foundation of China (No. LKLY26H28002), the Zhejiang Provincial Natural Science Foundation of China (No. LQ23H070005), and the Construction Fund of Key Medical Disciplines of Hangzhou (No. 2025HZZD06).

Conflicts of interest

None.