Role of adipokines in sarcopenia

Abstract

Sarcopenia is an age-related disease that mainly involves decreases in muscle mass, muscle strength and muscle function. At the same time, the body fat content increases with aging, especially the visceral fat content. Adipose tissue is an endocrine organ that secretes biologically active factors called adipokines, which act on local and distant tissues. Studies have revealed that some adipokines exert regulatory effects on muscle, such as higher serum leptin levels causing a decrease in muscle function and adiponectin inhibits the transcriptional activity of Forkhead box O3 (FoxO3) by activating peroxisome proliferators-activated receptor-γ coactivator -1α (PGC-1α) and sensitizing cells to insulin, thereby repressing atrophy-related genes (atrogin-1 and muscle RING finger 1 [MuRF1]) to prevent the loss of muscle mass. Here, we describe the effects on muscle of adipokines produced by adipose tissue, such as leptin, adiponectin, resistin, mucin and lipocalin-2, and discuss the importance of these adipokines for understanding the development of sarcopenia.

Introduction

At present, all countries worldwide are experiencing an obvious and unprecedented trend of population aging. In the past 60 years, the proportion of people aged 60 years and older has only increased from 8% to 10%. In the next 40 years, this group is expected to increase to 22% of the total population.^[1] The process of human aging is often accompanied by gradual changes in skeletal muscle mass, metabolism and function. Muscle mass and strength usually increase with age in youth, remain the same in middle age, and then decrease with age.^[2] In 1989, Irwin Rosenberg coined the term “sarcopenia” (Greek) to describe the age-related loss of muscle mass.^[3] In 2016, sarcopenia was recognized as a disease, and its code is ICD-10-CM (M62.84).^[4] Decreases in the muscle strength and strength of elderly individuals with sarcopenia often leads to various adverse outcomes,^[5,6] such as physical disability, inconvenience, poor quality of life, and death.

Adipose tissue plays a key physiological role in maintaining metabolic homeostasis in the body. Since the discovery of leptin, people's understanding of fat has further improved.^[7] Fat is now assumed to synthesize and secrete hundreds of factors—the “hormones” known as adipokines, such as leptin, adiponectin (ApN), visfatin, resistin, chemerin, interleukin 6 (IL-6), lipocalin-2 (LCN2), and tumor necrosis factor-α (TNF-α).^[8] The overall effect of adipokines on metabolic events is clear, but their effects on muscle and sarcopenia remain unclear. This review will discuss in detail the deep connection between fat and muscle. As an endocrine organ, what effects do adipokines secreted by fat exert on muscles? Researchers have not clearly determined whether adipokines have potential applications in the treatment of sarcopenia.

What Is Sarcopenia?

In the 1980s, sarcopenia was first described as an age-related decrease in lean body mass, which affected the body's exercise capacity and nutritional status.^[3] With in-depth research on sarcopenia, it has been identified as a progressive and widespread skeletal muscle disease characterized by an accelerated loss of muscle mass and function. This concept of sarcopenia was formally recognized by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) and the Asian Working Group on Sarcopenia (AWGS) in 2019.^[9,10]

A recent meta-analysis (total n = 692,056, average age: 68.5 years) found that the prevalence of sarcopenia varied from 10% to 27%, and the prevalence of severe sarcopenia ranged from 2% to 9%. People over 80 years old and people living in nursing homes or hospitals were more susceptible to this disease.^[11,12] Patients with sarcopenia not only suffer from a loss of muscle strength but also face mobility impairments that reduce their quality of life. As a result, they are at higher risk of morbidity (falls, fractures, and metabolic diseases) and mortality.^[5,6,13] Sarcopenia often occurs in obese patients and is called sarcopenic obesity.^[14] The main cause of sarcopenic obesity is age-related changes in metabolism and body composition, as well as the presence of obesity factors and physical diseases that are accompanied by aging. In this process, crosstalk among biologically active muscle tissues forms a negative feedback loop, thereby promoting a gradual increase in body fat mass and a reduction in lean body mass and muscle strength.^[15] Once the focus is on obesity, sarcopenia may be ignored, leading to undesirable consequences, such as accidental falls. Scott et al^[16] found that an assessment of muscle function may help predict the risk of falls among obese patients. When sarcopenia is accompanied by weight loss, the risk of death is substantially increased compared with sarcopenia alone.^[17]

Existing evidence suggests that exercise (resistance training and whole-body vibration associated with squatting exercises) plus nutrition (branched-chain amino acids, vitamin D, whey protein, soy milk, and milk) interventions improve muscle strength and function and exert different effects on muscle mass to achieve the purpose of reversing sarcopenia.^[18–25] In recent years, in-depth studies of adipokines have discovered their effects on muscles through endocrine pathways. In a study of 189 elderly people diagnosed with sarcopenia according to the AWGS2 (2019), their body mass index (BMI) and serum leptin levels were low.^[26] A study included 460 participants, 16.08% and 23.91% of whom suffered from sarcopenia and dynapenia, respectively. Serum leptin levels were negatively correlated with muscle strength but positively correlated with muscle mass; namely, a higher blood leptin level was associated with a reduced risk of sarcopenia and an increased risk of dynapenia,^[27] consistent with the results described above. ApN inhibits the transcriptional activity of Forkhead box O3 (FoxO3) by activating peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increasing insulin sensitivity, thereby preventing the loss of muscle mass.^[28,29] These results illustrate the potential applications of adipokines as treatments of sarcopenia. Therefore, a better understanding of the molecular mechanisms of the messengers produced by adipose tissue will help researchers develop new treatments for sarcopenia in the future.

Adipokines and Their Effects on Muscle

Adipose tissue is mainly comprised of a large number of clusters of fat cells. The aggregated adipose tissue is divided into fat lobules by a thin layer of loose connective tissue, and it is widely distributed under the skin of the human body and around the internal organs. Three types of adipose tissue are present in the mammalian body: white adipose tissue that stores energy, brown adipose tissue that maintains body temperature and energy balance, and beige adipose tissue that is found within some white adipose depots and shares many morphological and functional features of brown adipose.^[30,31] Adipose tissue is a special structure in the human body that plays a key physiological role in maintaining metabolic homeostasis. In 1994, leptin secreted by fat was discovered to signal the energy state of the central nervous system,^[7] confirming that adipose tissue is a key endocrine organ with high metabolic activity and initiating a new research field of adipocyte biology as a source of secreted molecules.

To date, more than 600 proteins secreted from fat cells or their surrounding extracellular matrix have been detected in adipose tissue, but this number will undoubtedly increase with further research.^[32,33] Leptin, ApN, visfatin, resistin, chemerin, IL-6, LCN2, and TNF-α participate in various immune responses and metabolic regulatory pathways by exerting autocrine, paracrine and endocrine effects, such as lipid metabolism, glucose metabolism, insulin secretion, inflammation, myocardial cell contraction, appetite and satiety.^[8,34,35] Regarding the current research results, leptin, ApN, resistin, lactone, LCN2 and other adipokines exert a certain regulatory effect on muscle and sarcopenia.

Leptin

Leptin, the first discovered adipose-derived factor, is mainly produced by white fat, but other tissues and cells, such as skeletal muscle cells and bone cells, also produce it.^[7,36,37] It plays an important role in controlling food intake, energy expenditure and the quality of adipose tissue.^[38] Leptin receptors are expressed in large quantities in musculoskeletal tissues. Upon interacting with leptin, they not only stimulate the growth of skeletal muscle but also trigger a series of physiological functions, such as increasing insulin sensitivity,^[39,40] and promoting the utilization of glucose and the breakdown of fat. The expression of leptin receptors is upregulated in response to muscle atrophy.^[41] A lack of leptin receptors in skeletal muscle or leptin resistance also causes muscle atrophy.^[42] Peripheral injection of leptin or injection of leptin into the ventromedial hypothalamus (VMH) of rodents increases glucose uptake and insulin sensitivity by red skeletal muscles,^[43,44] such as the soleus muscle. The possible mechanism is that leptin in the VMH preferentially activates adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), sympathetic nerves and beta adrenergic receptors (β-ARs) in tissues, which increase insulin signaling in red skeletal muscle in a β-AR-dependent manner and promote glucose uptake. AMPK activation is independent of the aforementioned effects and is not necessary.^[45] Activation of AMPK phosphorylates acetyl-CoA carboxylase (ACC),^[46] thereby inactivating it. Inactivation of ACC leads to a decrease in the level of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1, which leads to increased oxidation of fatty acids in skeletal muscle. AMPK also induces the translocation of fatty acid translocase/CD36 (FAT/CD36)^[47] to the plasma membrane, thereby stimulating the oxidation of fatty acids and releasing energy.

Leptin constitutes a negative regulator of oxidative stress and inflammation in the gastrocnemius muscle. In the presence of leptin deficiency, systemic and skeletal muscle oxidative stress, muscle inflammation and muscle atrophy may occur.^[48] Ob/ob mice exhibit reduced FoxO3a expression, increased PGC-1α levels, and downregulated atrophy markers muscle atrophy F-box and muscle RING finger 1 (MuRF1) in response to leptin administration, thereby inhibiting myofibrillar protein degradation. Leptin also inhibits the expression of myostatin and increases cyclin D1 and proliferating cell nuclear antigen (PCNA) expression to increase muscle cell proliferation,^[49] thereby inhibiting myofibrillar protein degradation and enhancing muscle cell proliferation [Figure 1]. In elderly mice, leptin treatment significantly increases the hindlimb muscle mass and extensor digitorum longus muscle fiber size. In addition, the expression of 37 micro ribonucleic acids (miRNAs) in mouse muscles was altered, especially the expression of miR-31 and miR-223, which were upregulated.^[50] Notably, miR-489 maintains muscle satellite cells in a quiescent state,^[51] while leptin disrupts this state and downregulates miR-489 expression to indirectly mediate muscle repair and regeneration.

Figure 1.

Leptin acts on muscles directly or indirectly by binding to leptin receptors to exert various biological metabolic effects, such as promoting muscle growth, inhibiting muscle atrophy, and increasing intramuscular glucose uptake and fatty acid oxidation. ACC: Acetyl-CoA carboxylase; AKT: Protein kinase B; β2-AR: β 2-adrenergic receptors; AMPK: Adenosine 5′-monophosphate (AMP)-activated protein kinase; FAT: Fatty acid translocase; FoxO3a: Forkhead box O3a; IGF-1: Insulin-like growth factor-1; MAFbx: Muscle atrophy F-box; MuRF1: Muscle RING finger 1; PCNA: Proliferating cell nuclear antigen; PGC-1α: Peroxisome proliferator-activated receptor-γcoactivator-1α; PI3K: Phosphatidylinositol-3-kinase; VMH: Ventromedial hypothalamus.

Leptin may also produce anabolic effects on skeletal muscle through insulin-like growth factor-1 (IGF-1).^[52] In elderly mice, the administration of leptin increases circulating and muscle-derived IGF-1 levels.^[53] A study in China revealed that participants with higher serum leptin concentrations had higher fat and muscle mass, and serum leptin levels were also positively correlated with the skeletal muscle mass index.^[27] When the serum leptin level is low, a certain correlation is observed with the decrease in the middle arm muscle area of elderly and infirm individuals.^[54] In summary, serum leptin levels may be an indicator of the long-term nutritional status. Patients with sarcopenia have lower obesity parameters and serum leptin levels, and thus a higher serum leptin level indicates a better nutritional status.

ApN

ApN, also known as 30 kDa adipocyte complement-related protein 30, was first discovered in 1995 and is a secreted adipose-derived factor that plays an important role in metabolism and inflammation.^[55–57] Large amounts of ApN are secreted by white adipose tissue,^[58] skeletal muscle cells,^[59] cardiomyocytes,^[60] liver parenchymal cells,^[61] and osteoblasts.^[62] ApN, including full-length adiponectin (fApN) and globular adiponectin (gApN), binds to adiponectin receptor 1 (AdipoR1) expressed in skeletal muscle and adiponectin receptor 2 (AdipoR2) expressed in the liver to perform various cellular and metabolic functions.^[63] In skeletal muscle, gApN has a higher affinity for AdipoR1 than fApN.^[64,65] ApN binds to AdipoR1 to activate AMPK through the Ca²⁺/Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK) and adaptor protein containing PH domain, PTB domain and leucine zipper motif-1/liver kinase B1 (APPL1/LKB1) pathways. APPL1 mediates ApN signaling by directly interacting with AdipoR1, and it acts as an anchor protein in the cytosol to increase the cytoplasmic localization of LKB1, which in turn activates AMPK.^[63,66–68] ApN also induces an increase in intracellular Ca²⁺ levels, thereby activating CaMKK in muscle cells, promoting AMPK phosphorylation, increasing the expression of PGC-1α, and promoting downstream activation of mitochondrial biogenesis [Figure 2].^[69] After AMPK is phosphorylated, it activates the sirtuin-1 (SIRT1) signaling pathway, thereby stimulating PGC-1α in the muscle to exert various biological metabolic effects.

Figure 2.

Adipocytes produce ApN which binds to AdipoR1 on the muscle surface and activates AMPK through the Ca²⁺/CaMKK and APPL1/LKB1 pathways to stimulate downstream processes, thereby inhibiting proteolysis, increasing myogenesis, promoting glucose uptake, inhibiting inflammation and regulating biological metabolism. However, macrophages are also converted from the M1 to the M2 state to promote the production of IL-10 and exert an anti-inflammatory effect. AMPK: Adenosine 5′-monophosphate (AMP)-activated protein kinase; ApN: Adiponectin; APPL1/LKB1: Adaptor protein containing PH domain, PTB domain and leucine zipper motif-1/liver kinase B1; CaMKK: Ca²⁺/calmodulin dependent protein kinase kinase; FoxO: Forkhead box O; GLuT4: Glucose transporter 4; IL-10: Interleukin 10; PGC-1α: Peroxisome proliferator-activated receptor-γ coactivator-1α.

Muscle stem cells, also known as satellite cells, remain in a quiescent state in healthy muscles. When muscles are damaged, these stem cells are activated, migrate, proliferate and differentiate into myoblasts and then fuse and repair the damaged muscle fibers or produce new muscle fibers.^[70,71] When skeletal muscle is injured, immune cells, including M1 macrophages, are recruited to the injured site and produce and release elastase that cleaves fApN into gApN to regulate and stimulate muscle production factors to promote muscle growth.^[72] gApN induces the expression of myogenic differentiation antigen (MyoD) to promote the proliferation and differentiation of muscle cells,^[73,74] promotes the survival of myoblasts and inhibits their apoptosis through AMPK-dependent mechanisms,^[75] and activates myogenin and myogenic regulatory factor 4 to promote muscle differentiation and stimulate the fusion of cells into multinucleated myotubes.^[76] At the same time, ApN upregulates Myf5, which stimulates the activation of satellite cells and recruits them to myotubes,^[77,78] where they produce specific metalloproteinases to degrade the extracellular matrix around muscle fibers and drive proteolytic migration to the injured site. Most gApN is produced locally by muscle cells, such as satellite cells and differentiated myoblasts, and it acts in an autocrine or paracrine manner.^[79] Its overexpression not only reduces the necrotic area after muscle injury but also increases the number of regenerated muscle fibers. A study of cardiomyocytes found that ApN overexpression significantly upregulated the mRNA levels of myogenic regulatory factors,^[80] increasing the lipid oxidation of cardiomyocytes and resulting in the conversion of muscle fibers from the glycolytic type (myosin heavy chain [MHC] IIb) to the oxidized type (MHC I).^[81]

In normal healthy muscles, ApN also regulates muscle sensitivity to insulin, inflammation, and oxidative stress. ApN phosphorylates AMPK and inhibits the production of p70 ribosomal S6 kinase 1 (p70S6K1), the enzyme that inactivates insulin receptor substrate 1,^[82] thereby increasing the sensitivity of cells to insulin; it also induces the translocation of glucose transporter 4 (GLUT4) to the plasma membrane and promotes glucose uptake.^[83]

ApN activates PGC-1α through the AMPK/SIRT1 pathway and increases the expression of some oxidative stress-detoxifying enzymes and molecules involved in fatty acid oxidation.^[69] Knockdown of AdipoR1, which specifically destroys the muscles of mice, decreases AMPK activity, decreases local levels of antioxidant enzymes, and decreases exercise capacity.^[84] ApN exerts powerful anti-inflammatory effects on human myotubes, which directly regulate the phenotype of macrophages, transforming them from a proinflammatory M1-like state to an anti-inflammatory M2-like state, in which they secrete the anti-inflammatory cytokine interleukin 10 (IL-10) to reduce the production of proinflammatory cytokines and exert anti-inflammatory effects [Figure 2].^[78,85,86] The muscles of ApN-deficient mice are more sensitive to oxidative stress, inflammation and apoptosis, which are exacerbated by acute or chronic inflammation.^[87,88]

LCN2

LCN2 is a secreted adipokine of the lipocalin subfamily that transports small hydrophobic molecules, lipids and iron.^[89–91] It is also known as neutrophil gelatinase-associated lipocali. It was originally identified in human neutrophils and some immune cells and tissues exposed to microorganisms in the respiratory and gastrointestinal tracts, and it is present at high levels in the circulation.^[92] According to a recent study, the expression of LCN2 in bones is at least 10 times higher than that in fat or any other tissues, indicating that it is also a bone-derived factor.^[93] Early studies found that LCN2 not only inhibits the growth of pathogenic bacteria by sequestering iron to play a role as part of the innate immune system but also participates in maintaining iron homeostasis.^[94] Further in-depth research on LCN2 revealed that it also played certain roles in insulin resistance, energy metabolism and adaptive thermogenesis.^[95] LCN2 expression is upregulated in obese or diabetic mice and humans.^[92,96] Mice lacking LCN2 not only exhibit impaired adaptive thermogenesis and diet-induced obesity but also experience a deterioration of insulin resistance.^[95] Therefore, LCN2 might represent a potential therapeutic target for controlling obesity-related type 2 diabetes.

Visfatin

Visfatin was originally presumed to be a cytokine-like molecule called pre-B cell colony enhancing factor,^[97] also called nicotinamide phosphoribosyltransferase, because it converts nicotinamide into nicotinamide mononucleotide and is also the rate-limiting enzyme of salvage biosynthesis of nicotinamide adenine dinucleotide.^[98] It was first reported in 2005 as a new adipokine expressed in visceral fat that mainly regulates glucose metabolism. Although this report was subsequently withdrawn, it was again confirmed as an adipokine in a follow-up study. Since then, research on the biological functions of visfatin has begun to be published.^[99] The previously introduced adipokine leptin in adipose tissue increased the production of visfatin in vivo or in vitro through the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways.^[100] In mouse C2C12 cells, visfatin increases the intracellular Ca²⁺ concentration to activate CaMKK^[101] and activates intracellular insulin receptors in a time-dependent manner, subsequently increasing the phosphorylation of AMPKα2 and its downstream targets ACC and Akt substrate of 160 kDa to increase glucose uptake in skeletal muscle.^[101]

Resistin

Resistin was first detected in mouse fat cells and promoted insulin resistance, hence the name.^[102] However, resistin is expressed at low levels in human fat cells, and the main source of human resistin is macrophages.^[103] Studies have found that human resistin has no direct effect on the insulin sensitivity of muscle cells.^[104] However, it may affect the insulin sensitivity of muscle cells by inhibiting myogenesis and stimulating the proliferation of myoblasts.

Adipokines as Therapeutic Targets for Sarcopenia

A large number of scholars have focused on adipokines and found that they exert varying effects on cancer,^[105,106] heart disease,^[107] neurological disease,^[108,109] metabolic disease^[110] and orthopedic disease (intervertebral disc degeneration, osteoarthritis, and rheumatoid arthritis).^[111–114] In terms of muscle diseases, such as sarcopenia, some adipokines levels change during their development. We evaluated the effect of adipokines on sarcopenia in detail here.

Leptin

As shown in recent studies, serum leptin levels are negatively correlated with muscle function (handgrip strength and gait speed).^[27,115,116] For example, in a cohort study, Lana et al^[116] found that a higher serum leptin concentration increased the risk of functional decline in the elderly, especially muscle weakness. Premenopausal women with a higher baseline serum leptin concentration are more likely to have decreased muscle strength and physical function deterioration than those with a lower baseline serum leptin concentration.^[115] Based on these results, higher serum leptin levels would cause a decrease in muscle function. To date, two explanations have been provided for these effects. One is leptin resistance that mainly manifests as hyperleptinemia and is common in obese individuals.^[117] Leptin resistance weakens normal leptin signal transduction, impairs the oxidation of fatty acids in muscle^[118] and increases the infiltration of intermuscular fat,^[119,120] which ultimately leads to skeletal muscle dysfunction.^[121,122] The decreased rate of fatty acid oxidation in the skeletal muscle cells of individuals with insulin resistance and obesity is another cause of higher serum leptin levels, which would lead to the accumulation of excess lipids,^[123] thereby impairing muscle quality and further affecting muscle strength.

Whether in men or women, a higher serum leptin is related to a reduction in the risk of sarcopenia,^[27] according to a research team. In contrast, the low serum leptin concentration detected in chronic hemodialysis patients is an independent predictor of sarcopenia. At the same time, an increase in leptin levels may induce the production of the inflammatory cytokines IL-6 and TNF-α, and high levels of inflammatory factors are key factors causing insulin resistance, which would reduce muscle mass and strength.^[123–125] Insulin resistance is also a key mechanism in sarcopenia obesity;^[15] therefore, leptin may be an important component in the pathogenesis of sarcopenia obesity. A cross-sectional analysis of 4062 participants showed that serum leptin levels were positively correlated with a reduced muscle mass, obesity and BMI,^[126] indicating that leptin may be a risk factor for a reduced muscle mass and obesity. The explanation for this difference may be the different effects of leptin on different people, such as obese individuals, hemodialysis subjects, the elderly, and people of various ethnicities. A recent study of a mouse Cystinosin (Ctns)^−/− model lacking a functional cystine protease gene reported that a pegylated leptin receptor antagonist (PLA) binds to the leptin receptor but does not activate it. This interaction reduces the mRNA expression of negative regulators of skeletal muscle mass (such as Atrogin-1, Murf-1, myostatin and the inflammatory cytokines IL-1β, IL-6 and TNF-α),^[127] and at the same time, the expression of myogenic factors (MyoD, myogenin and paired box 7 (Pax-7)) is increased. PLA treatment increases the muscle fiber size of Ctns^-/- mice and reduces fat infiltration into the muscles, thereby improving the lean body mass and muscle function of Ctns^-/- mice. Therefore, in obese patients, leptin receptor antagonists might reduce muscle atrophy and improve muscle function. In future research on muscle-related diseases, both leptin and leptin receptor antagonists are potential therapeutic targets.

ApN

The expression of atrophy-related genes (atrogin-1 and MuRF1) that substantially reduce muscle mass is the main cause of sarcopenia. FoxO induces the expression of these genes to promote protein degradation.^[29] ApN inhibits the transcriptional activity of FoxO3 by activating PGC-1α and sensitizing cells to insulin, thereby preventing a decrease in muscle mass. Similarly, in some animal experiments, ApN exerted a protective effect on muscles, and the level of ApN was negatively correlated with the risk of sarcopenia. In a mouse model of accelerated aging,^[128] the ApN/AdipoR1-AMPK axis mediated the effect of exercise on inducing the proliferation of satellite cells and improved the exercise strength of old mice. In a sarcopenia model established in ovariectomy mice,^[28] ApN or its mimics reversed the symptoms of sarcopenia and increased muscle mass by stimulating MyoD and inducing the expression of PGC-1α. gApN activates AMPK and protein kinase B (AKT), activates PGC-1α and inhibits the expression of FoxO transcription factors, effectively preventing the reduction in the myotube area and reducing muscle atrophy, as observed in a dexamethasone-induced muscle atrophy model.^[129] In the elderly, high serum ApN levels are associated with a low BMI, low skeletal muscle mass, low muscle density, increased amounts of fat and poor physical function.^[130,131] In a recent prospective study, Biercewicz et al^[132] found that among 88 elderly women, women who were at risk of malnutrition and had reduced skeletal muscle had higher levels of ApN than well-nourished women. ApN levels are high in patients with sarcopenia, but this finding is not consistent with the positive effect of ApN on muscles. Based on this result, high ApN levels are not the cause of sarcopenia but may be associated with ApN resistance or an increase in the confounding effect of ApN with age. This hypothesis requires further exploration and study. In conclusion, based on these findings, ApN may help manage or prevent the occurrence of sarcopenia and its metabolic sequelae.

LCN2

The focus of LCN2 research has shifted to muscle tissue. Recently, some studies have shown that the number and activation rate of satellite cells in LCN2⁻/⁻ mice aged 5–7 months after acute muscle injury are substantially reduced; in this case, a lack of LCN2 will reduce the proliferation of satellite cells and delay or even prevent damage repair after acute muscle injury.^[133] However, the muscle function of mice lacking the LCN2 gene is normal if the muscles are not damaged, although the diameter of their muscle fibers is smaller than that of normal mice.^[134,135] The upregulation of LCN2 after acute high-intensity exercise in humans is positively correlated with Dkk1, which reduces muscle production.^[134] LCN2 treatment not only reduces the myogenic differentiation of mouse C2C12 myoblasts but also upregulates the expression of the bone morphogenetic protein 2 gene of the TGFβ superfamily and subsequently prevents the myogenic differentiation of myoblasts in vivo.^[135] Thus, LCN2 may decrease myogenic differentiation when its expression increases. Compared with lean littermates, the expression of the LCN2 mRNA in the skeletal muscle of ob/ob mice with sarcopenia is increased, and iron accumulates in the muscles.^[136] Therefore, LCN2 is also a candidate target for future studies on the mechanism of sarcopenia.

Visfatin

Visfatin induces a time-dependent increase in GLUT4 mRNA and protein levels in C2C12 cells, and activation of the AMPKα2-p38 MAPK signaling pathway increases GLUT4 translocation, followed by an increase in skeletal muscle glucose uptake.^[101] Therefore, visfatin may function as a cytokine in muscle and affect the growth and metabolism of skeletal muscle. According to previous studies on muscle fibers, MHC isoforms are important indicators of muscle fiber types.^[137] Among them, MHC I is related to slow-twitch (Type I) muscle fibers, while MHC IIa and MHC IIb are mainly related to fast-twitch (Type IIa and IIb) muscle fibers. Visfatin also increases the expression of MHC in C2C12 myotubes by inhibiting the AMPK-FOXO1 signaling pathway.^[138] Studies aiming to explain the role of visfatin in skeletal muscle myogenesis may provide new insights into the mechanism of obesity-related skeletal muscle diseases.

Resistin

Obese subcutaneous adipose tissue secretes a large amount of resistin, which not only promotes the accumulation of lipids in muscle cells in the myotubes but also changes the metabolism of myotubes by enhancing the oxidation of fatty acids in the muscles and increasing myotube respiration and ATP production. It also activates the classical nuclear factor kappa-B (NF-κB) pathway to damage myotube thickness and nuclear fusion, thereby affecting myogenesis, especially in elderly individuals.^[139] In animal experiments, recombinant resistin not only stimulates the phosphorylation of AKT and reduces glucose uptake in C2C12 and L6 myotubes^[140] but also reduces the uptake and metabolism of fatty acids by skeletal muscle cells by reducing fatty acid transport protein 1 (FATP1) expression, AMPK and ACC phosphorylation, and the cell surface CD36 content.^[141] However, few studies are currently investigating the role of resistin in sarcopenia.

Conclusions

With the advent of the increase in global aging, the incidence of sarcopenia will further increase. To date, treatment and prevention strategies for sarcopenia remain to be explored. Studies conducted in the past decade have shown that metabolic factors, especially adipokines that are produced in large quantities by fat tissue and fat cells, affect many disease processes. In this review, we explored their key roles in muscles. According to the current research results, leptin, ApN, resistin, visfatin and LCN-2 are related to sarcopenia. They may be used as potential biomarkers for the early detection of sarcopenia or for monitoring disease remission during treatment. Some future clinical or preclinical studies are necessary to comprehensively summarize the roles of adipokines in sarcopenia, which will have high clinical value. Adipokines may soon be used to predict the progression and severity of sarcopenia and even serve as new targets for treatments combating sarcopenia or other muscle diseases.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos.82272611, 82072506), the National Clinical Research Center for Geriatric Disorders (Nos.2021KFJJ02 and 2021LNJJ05), the National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation (No.2021-NCRC-CXJJ-PY-40), the Science and Technology Innovation Program of Hunan Province (No.2021RC3025), the Innovation-Driven Project of Central South university (No.2020CX045), the Program of Health Commission of Hunan Province (202204074879) and the Independent Exploration and Innovation Project for Postgraduate Students of Central South University (No. 2022ZZTS0906).

Conflicts of interest

None