Targeting ubiquitin-dependent mitochondrial autophagy and apoptosis in sarcopenia: the therapeutic potential of phytochemicals

Abstract

Sarcopenia is a progressive degenerative disease of skeletal muscle closely associated with aging, disuse, and chronic diseases, affecting approximately 10–16% of the global older adult population. Its core pathological basis lies in the disruption of skeletal muscle cell proteostasis and mitochondrial dysfunction. At the molecular level, excessive degradation of structural proteins mediated by the ubiquitin-proteasome system forms an intertwined vicious cycle with the inability of ubiquitin-dependent mitophagy to clear damaged organelles, ultimately triggering irreversible cell death programmes within an oxidative stress and inflammatory microenvironment. Due to the high complexity and molecular crosstalk within this cell fate-determining network, traditional single-target interventions often yield limited therapeutic efficacy. In recent years, phytochemicals (such as polyphenols, flavonoids, alkaloids, and coumarins) have demonstrated significant therapeutic potential in the field of sarcopenia due to their unique multi-target, multi-pathway synergistic regulatory advantages. This article reviews the dual-faceted regulatory mechanisms of ubiquitination in skeletal muscle mitochondrial quality control, protein hydrolysis, and apoptosis escape and provides an analysis of how phytochemicals achieve autophagy-promoting, anti-apoptotic, and anti-degradative skeletal muscle protection. However, oral bioavailability is often below 1%, microbiota-dependent metabolism, and the absence of phase III clinical trials have hindered the translational application of phytochemicals. This paper explores the use of nano-delivery systems to overcome the bioavailability bottleneck of phytochemicals, as well as translational application strategies based on the gut-muscle axis to reshape the in vivo metabolism of natural products. This review aims to provide a solid theoretical foundation for the development of novel phytochemical-derived drugs targeting ubiquitination and apoptosis networks and to chart a course for reversing skeletal muscle ageing and enhancing human healthspan.

Introduction

Sarcopenia is a progressive, systemic degenerative disease of skeletal muscle prevalent among the elderly and patients with chronic conditions [1–4]. It severely impairs motor function, increases frailty, and serves as an independent risk factor that substantially elevates all-cause mortality [5, 6]. The maintenance of muscle mass relies heavily on proteostasis [7, 8], but aging and stress disrupt this balance [9], leading to profound structural degeneration [10, 11]. Furthermore, as a highly energy-consuming, terminally differentiated tissue, skeletal muscle is highly dependent on mitochondrial function. The intracellular mitochondrial regulatory network serves not only as a hub for energy metabolism but also as a key target for regulating cell survival and apoptosis signaling [12–14].

In the progression of sarcopenia, mitochondrial dysfunction and abnormal protein degradation form a vicious cycle, with ubiquitination acting as a key molecular regulatory mechanism [15]. Aging and metabolic stress cause an overload of reactive oxygen species (ROS) [16, 17]. While healthy cells rely on ubiquitin-mediated mitophagy to clear damaged organelles [18], severely impaired autophagic flux in sarcopenia causes dysfunctional mitochondria to accumulate, ultimately triggering apoptosis [19, 20]. Concurrently, excessive oxidative stress and inflammaging abnormally activate the ubiquitin-proteasome system (UPS) [21], which upregulates specific E3 ligases, accelerates the degradation of core contractile proteins, and exacerbates muscle atrophy [22, 23]. Dysregulation resulting from impaired mitochondrial autophagy clearance and excessive UPS-mediated degradation severely disrupts protein homeostasis and energy metabolism in skeletal muscle cells, leading to muscle fiber atrophy and functional decline.

Prospective cohort studies indicate that greater dietary intake of flavonoids and polyphenols among older adults is associated with a reduced risk of physical decline and frailty [24]. In parallel, consumption of antioxidant-rich foods has reduced inflammatory markers and modest improvements in muscle function [17]. Traditional single-target chemical drugs face significant limitations in treating sarcopenia, including limited efficacy and systemic side effects [25]. Consequently, plant-derived phytochemicals (such as polyphenols and flavonoids) have demonstrated tremendous therapeutic potential due to their high safety profile and multi-target regulatory capabilities [26, 27]. These natural compounds activate energy sensors like SIRT1 and AMP [28, 29], restore the damaged PINK1/Parkin mitophagy pathway, inhibit abnormal UPS activatio [30], and directly modulate apoptosis networks [31]. Furthermore, active phytochemical metabolites generated by enzymatic hydrolysis via gut microbiota (e.g., urolithins) offer systemic anti-aging protection to distal skeletal muscles through the gut-muscle axis [32].

In recent years, there has been a prominent increase in in vitro and in vivo studies investigating the efficacy of phytochemicals in delaying skeletal muscle aging. Although previous reviews have outlined the potential of these compounds in managing sarcopenia, none have integrated the ubiquitination network with apoptosis and the multi-target regulation of phytochemicals, nor have they systematically linked nanodelivery with microbiome biotransformation. This review introduces a mechanism to the delivery framework; We evaluate the ubiquitination system by contextualizing it as a bifurcated regulatory node that drives both protective mitophagy mediated by PINK1/Parkin and pathological degradation via the UPS. These opposing forces are integrated with oxidative stress, inflammaging, and apoptosis to construct a unified network regulating skeletal muscle cell survival, atrophy, and overall proteostasis. Instead of providing a conventional inventory of isolated compounds, we categorize representative phytochemicals based on their convergence upon core molecular hubs, thereby elucidating their multitarget synergistic actions. Furthermore, to overcome the inherent pharmacokinetic limitations of these natural agents, we critically assess engineered nanodelivery systems and gut microbiome biotransformation as complementary translational strategies. By delineating the complete translational continuum, spanning molecular targets, active phytochemicals, formulation strategies, tissue exposure, and ultimate therapeutic responses, this review establishes a cohesive roadmap for developing natural antisarcopenia therapeutics with robust multitarget regulatory capabilities.

Literature search and selection strategy

To ensure objective synthesis and reproducible curation of the literature, a comprehensive literature retrieval was conducted across four electronic databases—PubMed/MEDLINE, Web of Science Core Collection, Embase, and Scopus—covering publications from January 2000 through February 2026, with a particular focus on the years 2020–2025.

Search query architecture

The search string was constructed using medical subject headings (MeSH) and text words combined via Boolean operators:

[(“sarcopenia” OR “skeletal muscle atrophy” OR “muscle wasting” OR “myofibrillar degeneration”) AND (“mitophagy” OR “mitochondrial quality control” OR “PINK1” OR “Parkin” OR “ubiquitin proteasome system” OR “MuRF-1” OR “Atrogin-1” OR “FoxO”) AND (“phytochemicals” OR “polyphenols” OR “flavonoids” OR “urolithin” OR “quercetin” OR “curcumin” OR “resveratrol” OR “trigonelline”) AND (“nanotechnology” OR “nanoparticles” OR “lipid nanoparticles” OR “nanomedicine” OR “targeted drug delivery” OR “gut-muscle axis”)].

Eligibility and exclusion criteria

Inclusion Criteria: (i) Peer-reviewed original research elucidating molecular mechanisms of mitophagy, proteasomal degradation, or apoptosis in muscle; (ii) Preclinical studies in rodent models of sarcopenia with quantitative reporting(iii) Nanomedicine formulations reporting concrete physicochemical data (size, PDI, zeta potential, encapsulation efficiency); (iv) Human randomized controlled trials (RCTs) investigating phytochemicals or metabolites in sarcopenia.

Exclusion Criteria: (i) Non-peer-reviewed conference abstracts and preprints; (ii) Studies using undefined, crude botanical concoctions lacking active constituent quantification; (iii) Publications without English full text.

The key molecular mechanisms of sarcopenia

The PINK1/parkin pathway and mitochondrial autophagy

Mitochondrial autophagy (mitophagy) is the central autophagy mechanism responsible for maintaining mitochondrial quality within cells [33]. The process in question is capable of specifically identifying and enveloping damaged or redundant mitochondria, with the subsequent transportation of these to lysosomes for degradation [14, 34]. In this intricate molecular cascade, ubiquitination plays a pivotal role in targeting and marking mitochondria. Among these pathways, the PINK1/Parkin pathway is currently the most extensively studied and plays a dominant role in the physiological mechanisms of skeletal muscle [35, 36]. Under normal physiological conditions, newly synthesized PINK1 protein is continuously transported to the inner mitochondrial membrane (IMM) via the TIM23/TOMM complex, where it is subsequently cleaved by inner membrane proteases such as PARL and rapidly degraded [37, 38]. It is noteworthy that to maintain mitochondrial quality in skeletal muscle fibers and the distal ends of nerve axons, Pink1 mRNA can be anchored to the outer mitochondrial membrane (OMM) via synaptotagmin SYNJ2 and its binding protein SYNJ2BP for local translation, thereby meeting the rapid response requirements of the autophagy process for the short-lived PINK1 protein [39, 40]. In the context of skeletal muscle aging, metabolic dysfunction, or oxidative stress, damaged mitochondria undergo membrane potential depolarization, thereby impeding the internalization of PINK1 [41]. At this stage, full-length PINK1 is found to be stably localized to the outer mitochondrial membrane, with the assistance of TOMM complexes such as TOMM70/TOMM20, and is activated through a process of autophosphorylation [42]. Beyond the PINK1/Parkin axis, receptor-mediated mitophagy operates independently of ubiquitin through direct LC3-interacting region (LIR) motifs. BNIP3 and NIX (BNIP3L) are upregulated in skeletal muscle under hypoxia, exercise, and disuse atrophy; FUNDC1 mediates hypoxia-induced mitophagy via Ser17 phosphorylation [43]. In aged muscle, receptor-mediated pathways may compensate for declining PINK1/Parkin flux.

Activated PINK1 directly phosphorylates ubiquitin molecules localized on the outer mitochondrial membrane, as well as the ubiquitin-like domain of Parkin in the cytoplasm [35]. This instigates a conformational rearrangement in Parkin, releasing it from its autoinhibitory state and promoting its translocation from the cytoplasm to the surface of damaged mitochondria [44]. Once activated and localized to the mitochondrial outer membrane, Parkin exerts E3 ubiquitin ligase activity, catalyzing the ubiquitination of various outer membrane proteins, including VDAC1 and MFN1/2, to form K63 or K48 polyubiquitin chains [45]. These polyubiquitin chains then specifically recruit autophagy receptor proteins containing ubiquitin-binding domains [46]. Structural biology studies indicate that the autophagy receptor OPTN can initiate autophagy by recruiting the TBK1 kinase to directly bind to the PI3K complex [47]. Furthermore, the adaptor proteins NAP1 and SINTBAD of TBK1 regulate the threshold for autophagy initiation through a competitive binding mechanism while also promoting the extension of the autophagosome membrane mediated by NDP52 [48].

In addition to the classical PINK1/Parkin pathway, recent studies have revealed the compensatory or synergistic roles of non-canonical ubiquitin networks in skeletal muscle mitochondrial autophagy. For instance, RBX2/SAG, the core catalytic subunit of the CRL5 complex, has been identified as a mitochondria-localized ubiquitin ligase capable of mediating mitochondrial ubiquitination in a non-Parkin-dependent manner, which is critical for maintaining mitochondrial respiratory homeostasis in cardiac and skeletal muscle [49]. Furthermore, the pro-autophagic protein AMBRA1 stabilizes PINK1 by interacting with the inner membrane protein ATAD3A, while the chaperone DJ-1 participates in the recruitment of OPTN downstream of the PINK1/Parkin pathway; these mechanisms collectively constitute a multilevel regulatory network for mitochondrial autophagy [50, 51]. In the pathological progression of sarcopenia, accompanied by aging or chronic disease-induced catabolism, the PINK1/Parkin-mediated autophagy flux in skeletal muscle is significantly suppressed, leading to impaired clearance of damaged mitochondria [18]. The dysfunctional mitochondria exhibit impaired ATP synthesis and become a source of excessive ROS production. This, in turn, exacerbates intracellular oxidative stress, leading to skeletal muscle cell atrophy and apoptosis.

Muscle protein degradation via UPS

Impaired mitochondrial autophagy results in energy metabolism disorders within skeletal muscle tissue, with the abnormal activation of the UPS as a pivotal mechanism underlying the excessive degradation of skeletal muscle structural proteins. The UPS represents the primary pathway in eukaryotic cells that is responsible for the clearance of short-lived proteins, misfolded proteins, and key regulatory proteins [52]. In skeletal muscle tissue, myofibrillar ring finger protein-1 (MuRF-1) and muscle atrophy F-box protein (Atrogin-1/MAFbx) are two specific E3 ubiquitin ligases that play key roles in the process of myofibrillar atrophy [53]. Under normal physiological conditions, the expression of both proteins is maintained at extremely low levels; however, under pathological and stress conditions such as aging, starvation, denervation, or tumor cachexia, their transcriptional levels are significantly increased [54]. MuRF-1 primarily targets and mediates the ubiquitin-mediated degradation of core contractile proteins such as myosin heavy chain (MyHC) and troponin, whereas Atrogin-1 primarily mediates the ubiquitination of myogenic transcription factors and protein synthesis initiation factors [55]. The effect of degrading structural proteins and inhibiting protein synthesis significantly accelerates the loss of skeletal muscle mass. Furthermore, the abnormal activation of the UPS in skeletal muscle is strictly regulated by upstream signaling networks, in which FoxO family transcription factors, particularly FoxO1 and FoxO3a, play a regulatory role [56]. In the context of physiological anabolic conditions, IGF-1 activates the PI3K/Akt/mTOR signaling pathway. Akt, in turn, induces FoxO to remain in the cytoplasm by phosphorylating it, inhibiting its transcriptional activity [30, 57].

In the pathological state of sarcopenia, the PI3K/Akt/mTOR anabolic pathway is suppressed, leading to the nuclear translocation of unphosphorylated FoxO, which directly binds to the promoter regions of Atrogin-1 and MuRF-1, resulting in a significant upregulation of their transcription levels [58]. Research has demonstrated that DUSP22 expression is substantially elevated in sarcopenia models; it can abnormally activate the JNK pathway in an Akt-independent manner, lifting the inhibition on FoxO3a and promoting muscle atrophy [59]. Conversely, the activation of SIRT1 inhibits the transcriptional activity of FoxO3a through deacetylation, as well as promotes anti-atrophic effects by activating the AMPK/PGC-1α pathway to enhance mitochondrial biogenesis [60]. Consequently, targeted intervention at the aforementioned phosphorylation and deacetylation modification nodes to block the excessive activation of the UPS represents a significant potential strategy for the clinical prevention and treatment of sarcopenia.

Ubiquitination in sarcopenia is a bifurcated, context-dependent process. Selective ubiquitination of damaged mitochondrial outer-membrane proteins, mediated by Parkin through K63/K48 linkages, is required for autophagic clearance. In contrast, excessive and non-selective ubiquitination of core contractile proteins, driven by hyperactivation of the E3 ligases MuRF-1 and Atrogin-1 downstream of FoxO and NF-κB signaling, causes myofibrillar breakdown and muscle atrophy. Ubiquitination is therefore not uniformly beneficial [61]. A therapeutic strategy must selectively promote mitophagy-associated ubiquitination while restraining the ubiquitination that targets contractile proteins for proteasomal degradation.

Autophagy impairment promotes apoptosis

In the mechanisms governing skeletal muscle cell fate, mitochondria play a central role in regulating autophagy and apoptosis signaling [62]. In instances where the PINK1/Parkin-mediated mitochondrial autophagy flux is inadequate in addressing excessive oxidative damage, cells initiate programmed cell death pathways, notably apoptosis [15, 16]. Mitochondria-dependent intrinsic apoptosis pathways are subject to strict regulation by the BCL-2 protein family. In conditions of stress, pro-apoptotic proteins undergo a conformational rearrangement and oligomerization, resulting in a substantial increase in MOMP [19, 63] This process further promotes the release of pro-apoptotic factors, such as cytochrome c, into the cytoplasm, where they assemble with Apaf-1 to form apoptosomes, triggering apoptosis [64].

Cells retain compensatory mechanisms to maintain local microenvironmental homeostasis during the early stages of apoptosis. MOMP-induced IMM protrusion can trigger atypical ubiquitin-mediated autophagy independently of the PINK1/Parkin pathway. This mechanism acts early in the apoptotic cascade by phagocytosing damaged mitochondria, preventing the leakage of pro-inflammatory mediators such as mitochondrial DNA and avoiding the onset of widespread tissue inflammation [65]. Furthermore, the traditional apoptotic executor Caspase family exhibits multiple non-apoptotic regulatory functions in the pathophysiological processes of skeletal muscle [66, 67]. Single-cell and molecular omics studies have demonstrated that the exogenous apoptotic core protein caspase-8 is capable of inducing astrocyte activation and tissue fibrosis via a non-apoptotic pathway in models of lipid metabolism disorders [68]. Under conditions of severe infection, Caspase-8 can also specifically cleave N4BP1 to lift its inhibition of NF-κB, thereby amplifying pro-inflammatory signaling cascades [69]. In the context of the aging process, mild activation of Caspase-3 has been observed to cleave intact actin complexes, albeit not to the extent that would typically induce full-blown apoptosis. This specific cleavage event is more readily recognized and degraded by the UPS, thereby accelerating the process of muscle fiber atrophy (shown in Fig. 1; Table 1).

Fig. 1.

The Pathological Network of Skeletal Muscle Cells in Sarcopenia

Table 1.

Regulatory networks dictating skeletal muscle cell fate

Pathway/Biological Process	Regulatory Mechanism	References
Mitophagy (PINK1/Parkin)	Expression downregulation drives mitochondrial damage and ROS accumulation	[35]
OPTN/NDP52/p62	Autophagic flux blockade and receptor recruitment failure	[74]
UPS	Aberrant activation accelerates myofibrillar degradation	[75]
FoxO1/FoxO3a	Dephosphorylation and Nuclear Translocation Drive Degradative Cascades	[30, 59]
Apoptosis	Proapoptotic Protein Oligomerization and Cytochrome c Release	[19, 63]
Caspase-9/Caspase-3	Overexpression Induces UPS Accumulation and Cell Death	[76]

The ubiquitin-dependent cell-fate network

The PINK1/Parkin mitophagy, UPS-mediated protein degradation, and apoptosis pathways do not operate as isolated, linear cascades. They are instead reciprocally coupled within an integrated, ubiquitin-dependent cell-fate network that sets the balance between skeletal muscle fiber survival and atrophy; mitochondrial dysfunction serves as the common upstream trigger. Excess mitochondrial reactive oxygen species simultaneously initiate PINK1/Parkin-dependent mitophagy as a compensatory response and, through FoxO and nuclear factor-κB activation, drive UPS-mediated degradation of contractile proteins [56]. When mitophagic clearance fails, damaged mitochondria undergo outer membrane permeabilization and activate caspase-3, whose sub-lethal activity directly cleaves actin into UPS-recognizable fragments, thereby linking apoptosis to accelerated proteolysis [67]. Concurrently, inflammaging cytokines sustain nuclear factor-κB signaling, which reinforces both UPS hyperactivation and mitochondrial oxidative stress, closing a self-perpetuating cycle [70].

Within this network, phytochemicals intervene at multiple nodes. Resveratrol enhances PINK1/Parkin-dependent mitophagic flux [71]. Quercetin inhibit FoxO3a nuclear translocation, thereby suppressing MuRF-1 and Atrogin-1 transcription [72]. Curcumin antagonize NF-κB and reduce inflammatory cytokine output [73].

Inflammatory disruption of intercellular communication

Inflammation in aging and metabolic dysfunction

Aging is frequently accompanied by chronic, low-grade activation of the immune system, a process known as inflammaging, which is one of the key factors disrupting protein homeostasis in skeletal muscle cells [4, 70]. In the elderly population and in patients with comorbid chronic diseases, such as chronic obstructive pulmonary disease and heart failure, persistently elevated pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, induce significant local oxidative stress in skeletal muscle by activating the receptor-mediated NF-κB signaling pathway [9, 22]. Furthermore, with advancing age, the expression level of MCUR1, an auxiliary protein of the unidirectional transporter responsible for regulating mitochondrial calcium uptake, is significantly downregulated [77]. The phenomenon under investigation has been shown to result in impaired mitochondrial Ca²⁺ uptake and reduced respiratory chain energy production. This process further exacerbates ROS accumulation, disrupting intracellular calcium homeostasis and triggering apoptotic cascades [78]. In addition to the impact of intrinsic biological processes of aging, exposure to environmental toxins has a significant exacerbating effect on the damage caused by oxidative stress in skeletal muscle tissue. In preclinical rodent models of transgenic SOD1(G93A) mice, excessive exposure to copper has been demonstrated to induce SOD1(G93A)-mediated mitochondrial dysfunction in skeletal muscle, resulting in ATP depletion and a substantial increase in the levels of lipid peroxidation products, such as malondialdehyde [79].

Aging and the stress microenvironment also reshape the muscle atrophy network through abnormal crosstalk between organs. In decompensated cirrhosis, abnormally secreted FGF21 from the liver enters the bloodstream and binds to the Klotho beta receptor on the surface of skeletal muscle satellite cells, thereby inhibiting the PI3K/Akt pathway and blocking the proliferation and myogenic differentiation of satellite cells, leading to severe secondary sarcopenia [80]. Impaired hepatic ureagenesis causes hyperammonemia, inducing muscle myostatin expression and autophagy-independent myofibrillar breakdown [81]. Ammonia detoxification consumes BCAAs, depleting BCAA pools and blunting mTORC1 activation [82]. Furthermore, portal hypertension drives bacterial translocation, endotoxemia, and TLR4–NF-κB-dependent muscle wasting [83]. In chronic obstructive pulmonary disease, damaged skeletal muscle cells release the secreted glycoprotein DKK3 via autocrine and paracrine mechanisms. DKK3 induces mitochondrial dysfunction and sarcolemmal atrophy through its cell surface receptor CKAP4, making it a potential blood biomarker for predicting and diagnosing sarcopenia [84, 85]. In osteoarthritis-associated muscle pathology, the exacerbation of abnormal matrix mineralization also involves secreted phosphoprotein 1 blocking PINK1/PARKIN-mediated autophagy clearance via the ITGα5/β1 receptor [86]. The aforementioned systemic endocrine and metabolic disorders, in conjunction with the deterioration of the local microenvironment, severely impair the endogenous repair capacity and compensatory mechanisms for maintaining homeostasis in skeletal muscle cells when they respond to pathological stress involving apoptosis and excessive ubiquitin-mediated degradation (shown in Table 2).

Table 2.

Key molecular pathways and pathological mechanisms driving sarcopenia

Influencing factors	Molecular mechanisms changes	Impact on Skeletal Muscle and Organelles	References
Inflammaging	NF-κB Activation and SIRT1/Ak/ mTOR Inhibition	Ubiquitin Ligase Upregulation, Muscle Structural Degradation	[22]
Environmental Toxicology and Exposure	Induces MOMP and mitochondrial overload, disrupting PINK1/Parkin	Impaired autophagy leads to ATP depletion and the accumulation of lipid peroxides	[93]
Abnormal Secretion	Inhibition of PI3K/Akt signaling blocks autophagy via the ITGα5/β1 receptor	Impaired Myogenesis Promotes Satellite Cell Apoptosis and Matrix Calcification	[80, 94]
Dysbiosis	Inhibiting PINK1 flux disrupts the system’s energy homeostasis	Deterioration of mitochondrial function, loss of skeletal muscle mass, and impaired function	[95]

Organelle dysfunction and programmed cell death

Conventional wisdom has long posited that the loss of skeletal muscle cells in sarcopenia is predominantly attributable to apoptosis. However, recent multi-omics studies have revealed that the pathological process of sarcopenia involves the synergistic action of multiple programmed cell death mechanisms, including pyroptosis, necroptosis, and ferroptosis [70]. Taking pyroptosis as an example, this process is primarily mediated by the NLRP3 inflammasome and caspase-1, leading to the massive release of pro-inflammatory cytokines and cell membrane lysis [87]. In models of skeletal muscle aging, accompanied by downregulation of LAMP-2 A and impaired chaperone-mediated autophagy, the NLRP3 accumulates abnormally and induces pyroptosis, accelerating muscle fiber loss. However, supplementation with myogenic factors such as CTRP9 can effectively alleviate this pathological process by regulating the LAMP-2 A/NLRP3 axis [88]. Furthermore, ferroptosis is closely associated with skeletal muscle degeneration. In circumstances where the antioxidant enzyme GPX4 is suppressed, a multifaceted interplay between ferroptosis and apoptosis emerges [89].

In addition to programmed cell death, the disruption of inter-organelle communication networks is also an important mechanism underlying skeletal muscle aging. The mitochondria-associated endoplasmic reticulum (MAM) is a pivotal microstructure that facilitates the interaction between mitochondria and the endoplasmic reticulum [90]. This dynamic microstructure plays a role in regulating intracellular calcium transport and lipid metabolic homeostasis [91]. During skeletal muscle aging, the activation of endoplasmic reticulum stress leads to excessive MAM formation and abnormal Ca²⁺ influx; this induces severe mitochondrial dysfunction but also further activates muscle atrophy signaling pathways dependent on the unfolded protein response [92].

Phytochemical modulation of mitophagy and metabolism

Activation of the PINK1 parkin pathway

Phytochemicals, a class of multifunctional natural bioactive compounds, exhibit significant mitochondrial autophagy-activating effects and serve as key active molecules for restoring the control of skeletal muscle mitochondrial quality [96–98]. Among these, the natural polyphenolic compounds (urolithin A and urolithin B) derived from the metabolism of dietary tannins by the gut microbiota have become a hot topic in research on sarcopenia in recent years [99, 100]. In SOD1(G93A) transgenic mice, a model of amyotrophic lateral sclerosis in which copper exposure exacerbates pathological phenotypes, severe oxidative stress leads to ATP depletion and the accumulation of lipid peroxidation products, accompanied by a significant downregulation in the expression levels of key autophagy proteins such as PINK1, Parkin, and LAMP1. Intervention with urolithin A effectively upregulates the expression of these autophagy pathway proteins, reverses mitochondrial dysfunction, and significantly improves gastrocnemius muscle atrophy and impaired motor function [101]. In addition, urolithin B has been shown to promote cellular autophagy as well as activate the mTORC1 signaling pathway through its interaction with the androgen receptor, thereby inhibiting the UPS pathway and promoting protein synthesis within C2C12 myotubes [102]. The results of clinical studies demonstrate that urolithin A, a natural mitochondrial autophagy agonist with significant clinical translation potential, can effectively enhance mitochondrial energy metabolism and cellular senescence phenotypes in skeletal muscle of human patients diagnosed with sarcopenia [103].

In addition to the aforementioned components, various natural products such as polyphenols, flavonoids, and alkaloids have been shown in preclinical models to maintain skeletal muscle homeostasis by regulating the mitochondrial network [71]. For instance, in a streptozotocin-induced diabetic mouse model, resveratrol effectively alleviated abnormal skeletal muscle damage caused by excessive mitochondrial fusion and fission [71]. Not only does it activate PGC-1α-mediated mitochondrial biogenesis, but it also significantly alleviates diabetes-related muscle fiber atrophy by regulating the expression of cleaved caspase-3 and inhibiting the accumulation of LC3-II [53]. In addition, in models of ischemia-reperfusion or hypoxia-induced injury. In the event of the autophagy pathway being blocked via PINK1 gene knockdown or the application of mitochondrial inhibitors [104], the anti-inflammatory and neuromuscular protective effects of the aforementioned plant extracts were significantly reversed.

Reprogramming the NAD⁺ and autophagy

Recent studies have further revealed the direct role of specific phytochemicals in regulating NAD⁺ metabolism and mitochondrial homeostasis. Trigonelline, a natural alkaloid structurally related to nicotinic acid found in abundance in coffee beans and fenugreek seeds, has been shown to have significantly reduced serum concentrations in elderly patients with sarcopenia [105]. Exogenous supplementation with triterpenoid alkaloids can directly contribute to NAD⁺ biosynthesis via the Preiss-Handler pathway, thereby eliciting a substantial augmentation in intracellular NAD⁺ levels [106]. Elevated levels of NAD⁺ have been shown to activate the Sirtuin pathway, thereby improving mitochondrial respiratory function and biogenesis. This process has been demonstrated to delay age-related skeletal muscle atrophy and decline in exercise endurance, thus extending the healthy lifespan of affected individuals [107]. Coffee also contains other bioactive compounds; observational studies suggest that moderate coffee consumption is associated with lower mortality and better physical function [108] and may be associated with a reduced risk of sarcopenia [109]. Furthermore, Curcuma zedoaria extract, a traditional Chinese medicinal preparation, has been shown to downregulate pyroptosis levels by activating the PINK1/Parkin-mediated mitochondrial autophagy pathway, playing a protective role in maintaining the homeostasis of the neuromuscular network [110].

It is noteworthy that certain small-molecule compounds demonstrate intricate regulatory mechanisms in the context of mitochondrial autophagy. Spautin-1 was initially identified as an autophagy inhibitor, primarily by inhibiting the degradation of the PIK3C3/VPS34 complex mediated by the deubiquitinating enzymes USP10 and USP13 [111]. However, subsequent studies have demonstrated that Spautin-1 can bind to the mitochondrial outer membrane translocase complex TOMM70 and TOMM20, thereby impeding the transport of PINK1 to the inner mitochondrial membrane and its cleavage by the PARL protease, thereby promoting the stable localization of full-length PINK1 at the mitochondrial outer membrane [38]. This mechanism has been demonstrated to significantly promote PINK1/Parkin-mediated specific mitochondrial autophagy under non-autophagy-dependent conditions, demonstrating a protective effect against cellular degenerative diseases in experimental animal models. In summary, direct activation of the PINK1/Parkin signaling pathway, enhancement of NAD⁺ levels, and regulation of the ubiquitination modification network of key autophagy proteins are the mechanisms by which phytochemicals remodel mitochondrial quality control in skeletal muscle.

Phytochemical inhibition of the UPS and apoptotic cascades

Regulation of SIRT1/AMPK/FoxO signaling to prevent muscle wasting

In addition to inhibiting mitochondrial-mediated death signals, phytochemicals exert protective effects by interfering with nuclear-cytoplasmic transcriptional regulatory networks. Phytochemicals block the ubiquitination-mediated degradation pathway of skeletal muscle proteins at the transcriptional level by targeting the SIRT1/AMPK/FoxO signaling axis [28, 112]. Quercetin, a flavonoid compound that is found in a wide variety of plants, is a natural agonist of SIRT1 [113]. In a rat model of natural aging, the supplementation of quercetin effectively reverses age-related muscle weakness and atrophy. The activation of the PI3K/AKT signaling pathway by quercetin has been shown to inhibit the nuclear translocation of the catabolic factor FoxO, significantly downregulating its downstream target genes, leading to the downregulation of the transcriptional levels of the E3 ubiquitin ligases MuRF-1 and Atrogin-1 [72]. In addition, in a high-dose glucocorticoid-induced C2C12 cell damage model, quercetin was also to be capable of maintaining mitochondrial membrane potential homeostasis, inhibiting excessive apoptosis by reducing the Bax/Bcl-2 ratio, and restoring skeletal muscle cell survival and differentiation potential through ROS scavenging [114]. It has been demonstrated by other studies that TRIM16-mediated SIRT1 activation constitutes a pivotal regulatory mechanism in the alleviation of age-related oxidative stress and muscle fiber atrophy in skeletal muscle [60].

A similar mechanism has been observed in the natural compound umbelliferone. In a mouse model of type 2 diabetes, umbelliferone upregulates the expression of myogenic regulators such as MyoD and myogenin and improves mitochondrial homeostasis in skeletal muscle cells by activating the SIRT1/AMPK/PGC-1α signaling pathway, significantly inhibits UPS activation induced by the hyperglycemic microenvironment, effectively blocking FoxO3a nuclear translocation and its mediated upregulation of MuRF-1 and Atrogin-1, and maintains overall motor function in diabetic mice [115]. Other studies have shown that targeting the phosphatase DUSP22 can inhibit the JNK pathway in a non-Akt-dependent manner, maintaining the inactivated state of FoxO3a and preventing muscle atrophy [59].

Blocking inflammatory apoptosis to restore anabolism

Age-related chronic inflammation plays a pivotal role in the induction of apoptosis and excessive protein degradation in skeletal muscle cells. Phytochemicals have emerged as potent modulators capable of re-sensitizing cellular proteostasis networks and arresting mitochondrial-dependent apoptotic signaling cascades in degenerating tissues [4, 31, 116]. Avenanthramides (AVAs) are phenolic alkaloids that are unique to oats and which play a crucial role in modulating inflammation-induced skeletal muscle atrophy. In vitro studies indicate that AVAs pretreatment effectively blocks TNF-α-induced abnormal NF-κB activation, significantly reduces the secretion of downstream pro-inflammatory cytokines such as IL-6 and IL-1β, and effectively antagonizes TNF-α-induced upregulation of Atrogin-1 and MuRF-1 expression, thereby alleviating myotube atrophy [22]. Furthermore, in a mouse model of triple-negative breast cancer complicated by cachexia, curcumin significantly reduced overall ubiquitination levels in the gastrocnemius muscle by targeting the NF-κB/UPS signaling axis, improving cachexia-associated metabolic dysregulation phenotypes [73]. In a mouse model of disuse muscle atrophy induced by hindlimb unloading, curcumin delivered via a nanocarrier demonstrated a multi-target protective effect by synergistically inhibiting Caspase-1 activation, alleviating endoplasmic reticulum stress, and blocking necrotic apoptosis [117]. Age-related declines in anabolic hormones (testosterone, estrogens, IGF-1, and GH) downregulate baseline PI3K/Akt signaling, exacerbating baseline FoxO nuclear entry and blunting myogenic satellite cell responsiveness [118]. Phytochemicals that interface with steroid receptor signaling can partially bypass hormonal deficiencies to reactivate mTORC1-dependent protein synthesis.

In addition to the inhibition of skeletal muscle catabolism and excessive cell apoptosis, phytochemicals have also been demonstrated to effectively promote protein anabolic pathways. GABA can significantly improve the inflammatory aging phenotype in aged mice. In preclinical in vivo experiments in aged female mice, GABA promotes protein synthesis and improves motor function in the skeletal muscles of aged female mice by inhibiting the M1 polarization of macrophages, downregulating the expression of pro-inflammatory cytokines, increasing IGF-1 levels, reactivating the Akt/mTOR signaling pathway, and inhibiting the nuclear translocation of FoxO3a [119]. Furthermore, polysaccharides from Polygonatum, a species derived from the traditional Chinese medicine Polygonatum, regulate the structure of the mitochondria-associated endoplasmic reticulum membrane, maintaining intracellular calcium homeostasis. In the absence of endoplasmic reticulum stress, these agents effectively activate the PI3K/Akt/mTOR anabolic pathway, resulting in a substantial increase in the muscle fiber cross-sectional area in aged mice [120]. Concurrently, natural bioactive compounds such as fermented apple peel extract and exogenous nucleotides have also been shown to exert important synergistic protective effects by downregulating apoptosis markers, inhibiting the RAGE/MAPK/NF-κB pro-inflammatory signaling pathway, and blocking excessive protein degradation [121, 122] (shown in Fig. 2; Table 3).

Fig. 2.

Multi-target Synergistic Regulation by Phytochemicals

Table 3.

Phytochemical modulators in sarcopenia

Phytochemical	Natural Source	Key Molecular Target	Signaling Cascade	Experimental Model	Major Phenotypic Outcomes	Clinical Translation Status
Urolithin A	Microbial metabolite of ellagitannins	PINK1, Parkin, Beclin-1, FoxO3a	Mitophagy flux induction; UPS inhibition	Aged mice; Human elderly	Rescues mitochondrial respiratory function, increases muscle endurance and grip strength	Phase I/II Clinical Trials completed (improved 6-min walk distance; biomarker validation)
Quercetin	Apples, Onions, Capers	SIRT1, Akt, FoxO3a, Bax/Bcl-2	SIRT1/AMPK activation; PI3K/Akt survival; UPS suppression	STZ diabetic rats; Dexamethasone C2C12	Reduces MuRF-1/Atrogin-1, attenuates ROS-driven apoptosis	Phase II human trials in athletic performance and frailty
Resveratrol	Grapes, Polygonum cuspidatum	SIRT1, PGC-1α, Caspase-3	AMPK/SIRT1/PGC-1α; NF-κB blockade	STZ diabetic mice; Sarcopenic rats	Enhances mitochondrial biogenesis; suppresses caspase-dependent apoptosis	Phase II trials (mixed results due to rapid Phase II glucuronidation)
Curcumin / Nano-curcumin	Curcuma longa	NF-κB, IκBα, NLRP3, Atrogin-1	NF-κB/UPS; Caspase-1 pyroptosis inhibition	Hindlimb suspension mice; Cachexia models	Restores myofiber CSA; suppresses inflammatory proteolysis	Advanced Nanoformulations (Meriva, Theracurmin) under clinical evaluation
Trigonelline	Coffee beans, Fenugreek	Preiss-Handler pathway, NAD+, Sirtuins	NAD+/SIRT1/AMPK; PGC-1α	Aged mice; Sarcopenic human cohorts	Boosts mitochondrial ATP synthesis, restores muscle strength	Clinical biomarker correlation confirmed; pilot supplementation trials ongoing

Combining exercise training, particularly resistance and high-intensity interval training, with phytochemical supplementation can yield synergistic benefits. Exercise imposes mechanical loading that activates mechanotransduction and drives mTORC1-mediated myofibrillar protein synthesis [123]; phytochemicals, in turn, mitigate the exercise-induced oxidative burst, restrain excessive proteolysis, and prime mitochondrial quality through AMPK/SIRT1 signaling. Exercise also activates PINK1/Parkin-mediated mitophagy, AMPK/SIRT1, and mitochondrial biogenesis, and phytochemicals may amplify these responses [124].

The gap between preclinical evidence and clinical translation

Despite the preclinical promise of phytochemicals in mitigating sarcopenia, their clinical translation is severely constrained by unfavorable pharmacokinetics, complex concentration-dependent pharmacodynamics, and methodological inconsistencies across existing literature. A significant proportion of candidate molecules manifest biphasic or hormetic profiles. For instance, resveratrol has been observed to stimulate autophagy at low concentrations via SIRT1/AMPK signalling, yet paradoxically impairs autophagic flux at higher concentrations through off-target mTOR suppression [30, 53]. These non-linear dynamics are further compounded by significant metabolic and absorption barriers. Urolithin A has been demonstrated to effectively induce mitophagy in rodent muscle [101], however, clinical outcomes remain variable due to inter-individual divergence in the gut microbiota required for ellagitannin conversion [103, 125]. Phytochemicals such as curcumin are characterized by poor aqueous solubility, low gastrointestinal absorption, and rapid first-pass metabolism in the liver, leading to systemic bioavailability that is frequently less than 1% [126].

Beyond pharmacokinetic hurdles, clinical translation is limited by incomplete target identification and the precarious homeostatic of skeletal muscle proteostasis. Because the boundary between cytoprotective autophagy and maladaptive autophagic cell death is poorly demarcated, whether indiscriminate macroautophagy or selective mitophagy confers superior myofibrillar preservation continues to be debated. In myogenic tissue, the distinct roles of receptor-dependent mitophagy (BNIP3, NIX, FUNDC1) relative to ubiquitin-dependent PINK1/Parkin signaling also warrant clearer delineation. An equivalent trade-off governs the UPS: while indiscriminate proteasomal blockade induces overt myotoxicity by halting essential clearance of proteotoxic aggregates, phytochemicals generally elicit gentler, indirect transcriptional dampening. However, whether chronic, low-grade attenuation of UPS activity ultimately preserves muscle mass or inadvertently accelerates proteostatic failure remains an open question in aged cohorts.

Phytochemical metabolism and targeted delivery in the gut muscle axis

Phytochemical bioavailability

The oral pharmacokinetics of major phytochemicals differ markedly from their in vitro potency. Most phytochemicals exhibit poor oral bioavailability due to low water solubility, rapid gastrointestinal and hepatic metabolism, and active efflux by transporters such as P-glycoprotein. Absorption is often incomplete and variable, influenced by food matrix, gut transit time, and formulation and plasma concentrations after typical oral doses are typically low, and the circulating species are predominantly conjugated metabolites rather than the free parent compounds [127]. All major phytochemicals undergo extensive phase II conjugation in the intestinal epithelium and liver, so circulating species are predominantly conjugates: >90% of plasma quercetin is glucuronidated/sulfated [128], free resveratrol accounts for < 1% of total exposure [129], and curcumin is rapidly reduced to tetrahydrocurcumin by gut microbiota [130]. Ellagitannins are sequentially hydrolyzed to ellagic acid and then to urolithins by Gordonibacter and Ellagibacter species [131], while complex polyphenols are fermented into short-chain fatty acids that signal via GPR41/43 [132].

Tissue distribution further constrains translation. After oral dosing, free phytochemicals accumulate predominantly in the liver and kidney, where tissue concentrations exceed those in plasma, whereas penetration into skeletal muscle is poor and falls well short of the shown effectiveness in vitro. Allometric scaling from mouse to human is additionally confounded by species-specific differences in UGT isoforms, microbiota composition, and hepatic first-pass metabolism Most phytochemicals are GRAS at customary dietary levels, but high doses give rise to adverse effects. This risk is compounded in older adults on polypharmacy, because many phytochemicals modulate CYP450 isoforms and P-gp and may therefore precipitate clinically meaningful drug–herb interactions. Evidence for durable safety in sarcopenic elderly populations is also lacking: no randomized controlled trial has followed participants beyond 1 year, and the majority last only 8–24 weeks.

Nanomedicine overcomes bioavailability and tissue targeting barriers

Numerous in vitro and animal studies have demonstrated the significant clinical potential of phytochemicals in the field of sarcopenia. However, the poor water solubility and lack of tissue specificity of phytochemicals limit their clinical application [133–135]. To address the limited targeting capability of traditional liposomes, researchers have developed cell-membrane-coated biomimetic nanoparticles (shown in Fig. 3). By physically encapsulating or conjugating small-molecule bioactive compounds to liposomes, solid lipid nanoparticles, or natural polysaccharide complexes, their physicochemical stability and in vivo half-life can be significantly enhanced [136]. For instance, targeted nanocarriers constructed using fucoidan as a matrix can leverage their specific binding capacity to P-selectin to precisely deliver loaded active molecules, such as quercetin, to local inflammatory tissues [137]. Localized inflammation and oxidative stress in sarcopenia increase microvascular permeability, analogous to the EPR effect in solid tumors. Macrophage- or stem cell-membrane modified nanocarriers evade clearance by the mononuclear phagocyte system and utilize surface receptors to specifically home to the atrophied muscle microenvironment. This enables localized blockade of ubiquitination-degradation signals and reduces systemic off-target toxicity. For severe atrophy in specific muscle groups, transdermal delivery systems based on hydrogel microneedles allow for local in situ intervention. This system penetrates the stratum corneum, circumventing gastrointestinal metabolism and the hepatic first-pass effect. Additionally, it responds to specific stimuli in the diseased muscle microenvironment to achieve stimulus-responsive release of phytochemicals, suppressing muscle fiber atrophy while promoting the structural and functional repair of the neuromuscular junction.

Fig. 3.

Overcoming bioavailability bottlenecks: nanomedicine and the gut-muscle axis

With regard to targeted modification, contemporary nanodelivery systems present viable strategies for the precise regulation of apoptosis or metabolic pathways in specific cells. In an idiopathic pulmonary fibrosis model, researchers developed liposomes surface-modified with a VCAM-1-targeting peptide to deliver the BCL-2 small-molecule inhibitor venetoclax. Given the observation that pathogenic myofibroblasts exhibit high levels of VCAM-1 expression, these targeted liposomes have the capacity to specifically recognize and accumulate within diseased cells. This results in the selective induction of programmed cell death by means of antagonizing anti-apoptotic proteins, thereby effectively avoiding any potential toxicity to surrounding healthy tissues [138]. This targeted delivery concept provides insights for interventions in sarcopenia. In the future, it is anticipated that nanocarrier systems targeting specific surface receptors on skeletal muscle satellite cells or damaged slow-twitch muscle fibers will be developed [139]. These systems have the potential to facilitate the targeted delivery of autophagy agonists, such as urolithin A, to regions exhibiting mitochondrial dysfunction, or the enrichment of UPS inhibitors, such as quercetin, within oxidative stress microenvironments [140]. It is anticipated that specific remodelling and precise intervention of skeletal muscle homeostasis can be achieved within the systemic aging network.

Microbiome muscle crosstalk in natural product metabolism

A complex signaling network exists between the host gut microbiota and skeletal muscle homeostasis. Analogous to the “gut-lung axis” mediating mucosal immunity, the “gut-muscle axis” regulates proteostasis in distal skeletal muscle via the systemic immune network. Under aging or metabolic stress conditions, impaired intestinal physical barriers lead to the entry of lipopolysaccharide and other endotoxins into the bloodstream. Circulating endotoxins activate TLR4 receptors on skeletal muscle cells, inducing an inflammatory cascade, directly activating the FoxO/NF-κB pathway, and upregulating MuRF-1 and Atrogin-1 transcription, accelerating the ubiquitin-mediated degradation of myofibrils. Macromolecular phytochemicals such as polyphenols and ellagitannins serve as metabolic substrates for specific gut commensals, being converted into highly active small molecules like urolithin A or fermented into short-chain fatty acids (SCFAs) (shown in Fig. 3). These active metabolites upregulate the expression of intestinal tight junction proteins to repair the barrier and enter the skeletal muscle via the circulation. There, they inhibit the pro-inflammatory M1 polarization of macrophages and act as ligands to activate PINK1/Parkin-mediated mitophagy [125]. For instance, urolithin A, a representative compound in research on sarcopenia, is a metabolic end product generated through enzymatic reactions mediated by specific gut microbiota following the host’s intake of ellagitannin- and ellagic-acid-rich foods (e.g., pomegranate, walnuts, raspberries, and strawberries) [131]. Furthermore, short-chain fatty acids (SCFAs), including acetic acid, butyric acid, and propionic acid) produced by gut microbiota through the fermentation of dietary fiber are key signaling molecules for improving sarcopenia in the elderly [141]. In a model of accelerated aging in mice, supplementation with a mixture of SCFAs not only effectively reduced intestinal permeability and decreased levels of LPS and IL-1β in the circulatory system, but also significantly increased muscle fiber cross-sectional area, grip strength, and exercise endurance by activating the local skeletal muscle anabolic AKT/mTOR/S6K1 pathway and the AMPK/PGC-1α mitochondrial biogenesis pathway [132].

An imbalance in the gut microenvironment implies that external stressors can exacerbate skeletal muscle loss via the gut-muscle axis. Controlled in vivo experimental studies in murine models established that marked diurnal ambient temperature fluctuations destabilize the taxonomic equilibrium of the gut microbiota in middle-aged and aged mice. This environmental stress drives an abnormal bloom of pro-inflammatory bacterial genera while depleting short-chain fatty acid-producing taxa. The resulting systemic influx of microbial pro-inflammatory metabolites downregulates PINK1 and Parkin expression in distal skeletal muscle, impairing mitophagic flux and triggering muscle fiber atrophy [95]. The supplementation of probiotics rectifies these metabolic imbalances and enhances muscular function [142]. Supplementation with ellagitannin-metabolizing bacteria, represented by Gordonibacter urolithinfaciens and Ellagibacter isourolithinifaciens, facilitates the biotransformation of dietary ellagitannins into bioavailable urolithin A [143]. Similarly, supplementation with SCFA-producing bacteria, represented by Faecalibacterium prausnitzii and Akkermansia muciniphila, promotes butyrate-mediated restoration of intestinal epithelial tight junction integrity and improved skeletal muscle function [144]. In addition, the direct modulation of the gut microbiota in aged individuals has also demonstrated significant therapeutic effects. Fecal microbiota transplantation from young rats into aged rats has been demonstrated to effectively restore intestinal barrier function, increase levels of beneficial metabolites, significantly slow skeletal muscle interstitial fibrosis and atrophy, and improve mitochondrial function [145]. Furthermore, aging alters and reduces microbiome diversity and composition, affecting the metabolism and biotransformation of phytochemicals; this variability in the gut microbiota may account for the significant interindividual differences observed in experimental results. In summary, as key regulatory substrates for the gut microbiota, phytochemicals exert their anti-sarcopenic effects through complex interactions between natural bioactive compounds and the host microbiota. Consequently, future precision nutrition intervention strategies should consider individual gut microbiota profiles as a critical factor.

Conclusions and future perspectives

Conclusions

The development of sarcopenia involves a complex pathological network involving energy depletion, structural collapse, and multiple forms of cell death. The ubiquitination system plays a critical regulatory role in determining the fate of skeletal muscle cells. Moderate PINK1/Parkin-mediated ubiquitination of outer mitochondrial membrane substrates promotes the recruitment of autophagy receptors to initiate mitophagy, curbing apoptosis by eliminating sources of ROS [146]. However, in the context of aging and low-grade inflammation, an abnormally hyperactive UPS accelerates the degradation of skeletal muscle core contractile proteins by upregulating MuRF-1 and Atrogin-1, directly leading to muscle loss [23]. Targeting this pathological mechanism, phytochemicals such as polyphenols, alkaloids, and coumarins demonstrate intervention advantages through multi-target synergistic regulation. They can reshape signaling hubs such as SIRT1/AMPK/FoxO and PI3K/Akt/mTOR, not only promoting the autophagic clearance of damaged mitochondria but also blocking the nuclear translocation of NF-κB and FoxO3a upstream to curb excessive UPS activation [28, 30, 115]. Furthermore, by inhibiting MOMP and the caspase cascades, phytochemicals promote the restoration of anabolic processes in skeletal muscle cells, demonstrating the pharmacological value of natural products in the treatment of degenerative muscle diseases.

Limitations

Despite the promise of phytochemical modulators, their adoption into routine clinical practice remains constrained by several unresolved barriers. Most pharmacological evidence still derives from in vitro systems or rodent models, and adequately powered, large-scale randomized controlled trials are needed before these findings can be extended to patients. Pharmacology adds a second layer of difficulty: low aqueous solubility and extensive first-pass metabolism make it hard to reach therapeutically relevant concentrations in skeletal muscle, while the direct molecular targets of most phytochemicals remain largely unconfirmed. Study design and standardization raise a third set of concerns. Responses vary between primary and secondary sarcopenia; women and comorbid older adults are underrepresented in preclinical experiments; plant extracts lack standardization and batch-to-batch consistency; and no safety data extend beyond one year in sarcopenic populations. Until these issues are resolved, phytochemicals will remain promising preclinical candidates rather than evidence-based clinical interventions. Most preclinical work has been conducted in male rodents, introducing a substantial sex bias. Where both sexes have been examined, female rodents display higher estrogen receptor-mediated baseline mitochondrial quality control and distinct pharmacokinetics for polyphenol glucuronidation, reflecting sex-differential expression of hepatic CYP and UGT enzymes. Inflammatory tone also differs between sexes, and estrogen’s antioxidant effects may further modulate treatment response. On this basis, postmenopausal women may derive greater benefit from anti-inflammatory compounds, whereas men may respond more favorably to anabolic agents. Future studies should therefore include both sexes and report sex-disaggregated outcomes.

Future perspectives

In future research, integrate transcriptomics, proteomics, ubiquitinomics, metabolomics, and lipidomics with single-cell RNA sequencing and spatial transcriptomics to map, at cell-type resolution, how phytochemicals act in satellite cells, slow- and fast-twitch myofibers, motor neurons, and tissue macrophages. Network pharmacology will further build compound-target-pathway networks to screen multi-target phytochemical combinations and predict synergistic effects. AI-assisted drug discovery that combines graph neural networks with molecular docking holds promise for identifying novel phytochemical scaffolds targeting Parkin or deubiquitinases, while generative models can be used to design analogues with higher bioavailability. Precision medicine should first stratify patients by mitochondrial haplotype, UPS activity biomarkers, and inflammatory profiles, and then match them to appropriate interventions. Personalized nutrition can leverage gut microbiome profiles to estimate an individual’s urolithin-production capacity and, on that basis, customize combined ellagitannin or probiotic supplementation. Specific biomarkers, including DKK3, the myosin/cystatin C ratio, and SPP1, can enable real-time monitoring of intervention response. Finally, nano-targeted delivery systems and gut-muscle axis modulation should be further optimized to overcome bioavailability bottlenecks and advance the use of phytochemicals in the prevention and treatment of skeletal muscle aging.

Author contributions

Y. Z.: Design and planning of the study; critical review of the literature; drafting and editing of the manuscript; critical review of the manuscript; approval of the final version of the manuscript.P.W.: Critical review of the literature; drafting and editing of the manuscript; approval of the final version of the manuscript.All of the listed authors have reviewed this manuscript and have no objections to its content or the order of authorship and also unanimously agreed to submit it for publication.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

Not applicable. This narrative review involves no human or animal experimentation.

Consent to publish

Not applicable. This review contains no individual person’s data.

Consent to participate

Not applicable. No individual human participants were recruited or surveyed for this study.

Competing interests

The authors declare no competing interests.