During the aging process, chronic sterile inflammation is characterized by a mild yet persistent increase in pro-inflammatory factor levels, a phenomenon referred to as inflammaging (Antuña et al., 2022). Inflammaging influences the progression of sarcopenia through multiple mechanisms, such as cellular senescence, mitochondrial DNA damage and changes in adipose tissue and (Liang et al., 2022).

Cellular senescence leads to the secretion of a senescence-associated secretory phenotype (SASP), a complex of pro-inflammatory cytokines, chemokines, proteases, and growth factors (Hernandez-Segura et al., 2018). Pro-inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), activate the ubiquitin-proteasome system (UPS) and autophagy signaling pathways, thereby promoting catabolic processes, while simultaneously inhibiting the PI3K/Akt/mTORC signaling pathway, which reduces protein synthesis (Webster et al., 2020). Upon binding to tumor necrosis factor receptor 1 (TNFR1), TNF-α recruits tumor necrosis factor receptor type 1-associated death domain protein andTNF receptor-associated factor 2/5, leading to the activation of the IκB Kinase (IKK) complex. IKK phosphorylates IκBα, resulting in its ubiquitination and degradation, and subsequently releasing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) (Li et al., 2016). NF-κB binds to the promoter regions of muscle ring-finger protein 1 (MuRF1) and muscle atrophy f-box protein(Atrogin-1), upregulates their transcription (Schiaffino et al., 2013), accelerates protein degradation. Additionally, TNF-α activates jun n-terminal kinase, inhibits insulin receptor substrate 1, and blocks the PI3K/Akt signaling pathway, leading to the dephosphorylation of fork head box O3 (FoxO3) (Ko et al., 2023). Dephosphorylated FoxO3 translocates to the nucleus and directly binds to the promoters of MuRF1 and Atrogin-1, promoting their transcription. Furthermore, dephosphorylated FoxO3 upregulates the expression of Microtubule-associated protein light chain 3(LC3)and Beclin-1, stimulating the formation of autophagosomes (Zhang et al., 2023). In aged mice, geriatric satellite cells switch from reversible quiescence to p16^∧INK4a-driven senescence, secreting IL-6 and TNF-α (SASP) and leading to a 25 % reduction in myofiber cross-sectional area; genetic or pharmacological suppression of p16^∧INK4a or JAK/STAT signaling restores muscle regeneration (Sousa-Victor et al., 2014).

Transforming growth factor-β (TGF-β), as a critical component of the SASP, exerts significant influence on tissue repair, fibrotic processes, and aging-related mechanisms (Wang et al., 2024). TGF-β inhibits the proliferation and differentiation of muscle stem cells via the p38 Mitogen-Activated Protein Kinase signaling pathway, hindering muscle regeneration (Kim and Lee, 2017). TGF-β also activates autophagy-related genes such as LC3 and BCL2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) through the smad3 signaling pathway, leading to excessive autophagy and myofiber damage (Kim and Lee, 2017). With advancing age, adipose tissue accumulates ectopically within skeletal muscle, leading to intramuscular fat infiltration (Liang et al., 2022), which is a key characteristic of sarcopenia (Al Saedi et al., 2022). Intermuscular adipose tissue (IMAT) contributes to insulin resistance and inflammation (Beasley et al., 2009). Studies have demonstrated that increased thigh IMAT is associated with an elevated risk of type 2 diabetes and impaired glucose tolerance (Al Saedi et al., 2022). Additionally, higher levels of thigh IMAT are significantly correlated with increased Interleukin-6 (IL-6) and C-reactive Protein (CRP) levels in men (Beasley et al., 2009).

Mitochondrial dysfunction is a central pathological mechanism in age-related sarcopenia, characterized by progressive age-related declines in bioenergetic efficiency, leading to impaired ATP synthesis and compromised muscle protein anabolism (Kamarulzaman and Makpol, 2025). A decrease in the expression of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), has been reported in age-related sarcopenia. Clinical studies demonstrate a significant association between circulating PGC-1α concentrations and gait speed in older adults (Joseph et al., 2012). Experimental models further reveal that genetic upregulation of PGC-1α in injury-induced muscle atrophy models sustains mitochondrial density and contractile force (Southern et al., 2019). Furthermore, endurance training-induced mitigation of age-related mitochondrial dysfunctionis mediated through PGC-1α-dependent mechanisms, as evidenced by the complete abolition of these protective effects in PGC-1α−/− murine models (Leick et al., 2010). Furthermore, the findings reveal that in aged wild-type (WT) mice, PGC-1α expression was upregulated two-fold following training, accompanied by a 42% improvement in treadmill endurance. In contrast, knockout (KO) mice (mPGC-1α−/−) exhibited neither an increase in PGC-1α expression nor any functional improvement. Specifically, the time to exhaustion during treadmill testing in the WT training group increased by 42% (P < 0.01), whereas the KO training group showed only an 8% increase, which was not statistically significant. These results provide strong evidence that the enhancement of endurance resulting from exercise training is causally linked to PGC-1α upregulation and mitochondrial remodeling (Leick et al., 2010).

Mitophagy is essential for maintaining mitochondrial integrity, and its dysregulation exacerbates sarcopenia. Previous studies have highlighted the critical role of mitophagy in preventing disuse muscle atrophy. Examination of immobilized mt-Keima mice revealed significant decreases in muscle strength and atrophy in type IIA, IIX, and IIB muscle fibers, accompanied by a notable increase in mitophagy flux. Inhibition of mitophagy flux with colchicine exacerbated atrophy in type IIX and IIB fibers, along with a marked reduction in mitochondrial function and activation of apoptosis-related proteins CASP9 and CASP3 (Rahman et al., 2025). Mitophagy in mammals is regulated by PTEN-induced kinase 1 (PINK1) and parkin (Liu et al., 2021). Deletion of parkin reduces muscle mass and leads to poor physical function in older mice, while overexpression of parkin improves skeletal muscle function in older mice (Liu et al., 2021). Genetic deletion of PINK1 and parkin leads to dysfunction of mitophagy and mitochondria, muscle destruction, while increased mitophagy with overexpression of PINK1, parkin, and dynamin-related protein 1 in drosophila reduces age-related muscle dysfunction (Romanello, 2020). Since parkin and PINK1 regulate mitophagy and mediate sarcopenia-related muscle weakness, increases in the expression of these proteins may likely be a useful strategy to form a healthy mitochondrial network in skeletal muscles.

The etiology of sarcopenia is multi-factorial, with deterioration of neuromuscular junction (NMJ) as one of the major causes (Bao et al., 2020). The integrity and function of the NMJ, bridging the gap between the nervous and muscular systems, are pivotal for muscle strength input and reliable neural control. Consequently, NMJ has long been a focal point in researching skeletal muscle dysfunction and sarcopenia during the aging process (Arnold and Clark, 2023). A study examining the fidelity of NMJ transmission in hind limb muscles of male and female C57BL/6J mice across various ages revealed that NMJ transmission failure primarily manifests during the aging phase of mice, leading to reduced excitability of muscle fibers in these mice (Chugh et al., 2020). Furthermore, NMJ defects are closely correlated with hind limb grip strength, gastrocnemius muscle weight, loss of peak contractile torque, and loss of motor units (Padilla et al., 2021). Evidence from electrophysiological studies indicates age-related impairments in neuromuscular junction (NMJ) stability. Sarto et al. (2024) reported that, compared with young individuals, older adults exhibited a significant increase in near-fiber jitter on electromyography, suggesting a decline in conduction stability at the NMJ. These electrophysiological changes were accompanied by elevated levels of the C-terminal agrin fragment (CAF), alterations in caveolin-3 expression, and increased serum neurofilament light chain (NfL). Collectively, these neuromuscular alterations were associated with concomitant muscle atrophy and weakness (Sarto et al., 2024). Up porting the functional relevance of these observations, a longitudinal cohort study by Gilmore et al. (2017) further observed that near-fiber jitter increased by approximately 31%–43% during the progression from pre-sarcopenia to severe sarcopenia. Together, these findings suggest that NMJ conduction instability may serve as a sensitive biomarker for assessing sarcopenia severity.

The NMJ, serving as a critical synapse linking motor neurons and muscle fibers, undergoes progressive degeneration during aging. This degeneration is primarily characterized by structural deterioration, alterations in synaptic transmission function, and diminished plasticity, ultimately contributing to the decline in muscle mass and functional capacity. With advancing age, the presynaptic structure of the NMJ exhibits axonal denervation, reinnervation, and remodeling, along with changes in intramuscular nerve branching patterns (Iyer et al., 2021). In aged rodents, the NMJ becomes increasingly fragmented, marked by reduced synaptic folds, decreased numbers of presynaptic vesicles and nerve terminals, dispersed motor endplate regions, reduced density of acetylcholine receptors (AChRs), and diminished binding affinity of AChRs. These structural and functional changes may impair synaptic transmission efficiency, leading to denervation-induced muscle dysfunction and morphological alterations at the NMJ, such as increased endplate area, reduced synaptic folds, and decreased nerve terminal branches. Such modifications are likely to compromise the normal function of the NMJ. Factors such as reduced release of acetylcholine from presynaptic terminals and decreased sensitivity of postsynaptic membranes to AChRs further contribute to the decline in synaptic transmission efficiency, weakening the signaling for muscle contraction and resulting in reduced muscle strength (Taetzsch and Valdez, 2018). Although the NMJ possesses a degree of intrinsic plasticity that allows adaptive remodeling in response to neuromuscular diseases or injuries, this capacity diminishes with age, rendering the NMJ more susceptible to damage.

In recent years, the agrin/MuSK/LRP4 signaling pathway has been identified as one of the key regulatory mechanisms governing NMJ development and stability (Zong et al., 2012). Agrin, a glycoprotein secreted by motor neurons and a pivotal factor in NMJ formation, binds to low-density lipoprotein receptor-related protein 4 (LRP4) on the muscle membrane. This interaction activates muscle-specific kinase (MuSK), initiating a cascade of downstream signaling events that promote the clustering of AChRs on the postsynaptic membrane, thereby completing NMJ formation (Zong and Jin, 2012). Dysregulation or abnormalities in this signaling pathway may result in structural and functional impairments of the NMJ, potentially leading to neuromuscular disorders such as myasthenia gravis (Walker et al., 2021). Lahiri et al. (2019) observed that the gene expressions of acetylcholine receptor (AChR) subunits (Chrna1, Chrnb1, Chrne, Chrnd) and essential assembly factors, including Rapsyn and Lrp4, were significantly downregulated in the tibialis anterior muscle of germ-free (GF) mice, suggesting a potential impairment in AChR assembly. These alterations were reversed following colonization with conventional microbiota (C-GF). Furthermore, GF mice exhibited reduced gene expression of troponin, decreased grip strength, as well as diminished locomotor and upright activities (P < 0.05 to P < 0.001) (Lahiri et al., 2019). Collectively, these findings indicate that the absence of gut microbiota compromises neuromuscular junction (NMJ) function and muscle strength through disruption of AChR assembly and suppression of downstream contractile protein expression. Shi et al. (2024) conducted bidirectional two-sample Mendelian randomization (MR) and mediation analysis to suggest that elevated levels of Enterococcus faecium and reduced levels of Faecalibacterium prausnitzii are associated with a significantly increased risk of myasthenia gravis, mediated through decreased serum agrin concentrations and disruption of the agrin-MuSK-LRP4 signaling pathway. This pioneering study establishes, for the first time, the “gut microbiota–neuromuscular junction” causal axis at the human genome-metagenome interface, offering a mechanistic foundation for microbiota-targeted interventions in neuromuscular junction (NMJ)-related disorders.

The neuroendocrine system plays a core role in the occurrence and development of sarcopenia, influencing muscle mass and function through regulating muscle protein synthesis and degradation, energy metabolism, and inflammatory responses.

Growth hormone (GH), secreted by the anterior pituitary gland, stimulates the liver to synthesize growth factor-1(IGF-1) (Gharahdaghi et al., 2020), which promotes muscle protein synthesis by activating the PI3K/Akt/mTOR pathway. With aging, the secretion levels of GH and IGF-1significantly decline, leading to reduced muscle synthesis and atrophy (Hage and Salvatori, 2023). Research findings suggest that serum IGF-I levels in growth hormone (GH)-deficient (lit/lit) mice decline progressively with age and are more than fourfold lower than those in normal (lit/+) littermates, which maintain stable IGF-I levels up to 52 weeks. This is accompanied by a reduction in total IGF binding capacity in lit/lit mice, primarily due to decreased levels of IGF binding proteins, particularly IGFBP-3. Notably, a significant age-related reduction in protein percentage was observed exclusively in GH-deficient mice (Donahue and Beamer, 1993). The Snell dwarf mouse demonstrates a significantly higher myonuclear density in the soleus muscle compared to normal mice; however, the total number of nuclei is reduced relative to normal mice(Stickland et al., 1994). This phenomenon can be ascribed to the diminished secretion of growth hormone resulting from pituitary dysfunction, which consequently impairs muscle synthesis and development.

Sex hormones, such as testosterone and estrogen, are also crucial for maintaining muscle mass and strength. With aging, the levels of sex hormones gradually decline, leading to a reduction in muscle mass and strength. Testosterone promotes muscle protein synthesis and inhibits proteolysis primarily by activating androgen receptors in myonuclei and satellite cells. It also modulates key metabolic factors such as GH and IGF-1, which are essential for muscle repair and regeneration (Shigehara et al., 2022). Conversely, low testosterone levels exacerbate chronic inflammation and oxidative stress, leading to activation of the ubiquitin-proteasome system (UPS) and accelerated muscle protein degradation (Parahiba et al., 2020). Clinically, the reduction in testosterone levels in elderly men is closely associated with decreased muscle mass and strength, and testosterone supplementation has been shown to improve grip strength, leg strength, and overall physical function in sarcopenic individuals (Parahiba et al., 2020; Shigehara et al., 2022). Similarly, estrogen also plays an important role in maintaining muscle mass and function in women, and its decline can lead to muscle deterioration. Estradiol promotes beneficial effects on skeletal muscle by stimulating satellite cell proliferation and limits inflammatory stress-induced damage to skeletal muscle (Geraci et al., 2021). Studies have demonstrated that postmenopausal women experience a decline in estrogen levels, which contributes to reduced skeletal muscle function and increases the risk of sarcopenia (Lu and Tian, 2023).

Aging-related excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis results in elevated cortisol levels. Glucocorticoids bind to glucocorticoid receptors in skeletal muscle, thereby activating the UPS and autophagy-lysosomal pathway, which promotes muscle protein degradation (Schakman et al., 2008). Furthermore, chronic low-grade inflammation associated with HPA axis activation, characterized by increased levels of IL-6 and TNF-α as well as oxidative stress, exacerbates muscle damage (Manoli et al., 2005). Pro-inflammatory cytokines inhibit the IGF-1/PI3K/Akt signaling pathway, leading to reduced muscle protein synthesis. Excessive HPA axis activity suppresses the GH-IGF-1 axis, a critical pathway for maintaining muscle mass and satellite cell activity (Schakman et al., 2008). The age-related decline in GH and IGF-1 levels, coupled with HPA axis-driven cortisol elevation, creates a “catabolic-anabolic imbalance,” resulting in net muscle loss. Studies have demonstrated that physical performance in older adults is negatively correlated with elevated cortisol levels (Peeters et al., 2007; Figure 1).

Chronic low-grade inflammation is a mild yet persistent systemic inflammatory state that serves as a central pathophysiological link between gut microbiota dysbiosis and age-related sarcopenia (Antuña et al., 2022). With advancing age, the gut microbiota undergoes profound structural alterations, characterized not by unidirectional changes in individual bacterial taxa, but by a broader ecological imbalance, specifically, a decline in anti-inflammatory and protective microbial populations (including Lactobacillus, Bacteroides, Prevotella, and Faecalibacterium, a key producer of butyrate) alongside an aberrant expansion of potential pro-inflammatory genera such as Liminibacter and Escherichia-Shigella (Wang et al., 2025).

This specific microbial dysbiosis promotes systemic inflammation through a dual-pathway mechanism. The depletion of beneficial bacteria, particularly Faecalibacterium, results in markedly reduced production of short-chain fatty acids (SCFAs), such as butyrate. SCFAs serve not only as critical energy substrates for maintaining intestinal barrier integrity but also exert potent anti-inflammatory effects by inhibiting histone deacetylases and activating G-protein-coupled receptors including GPR43 and GPR109a. These actions lead to suppression of the NF-κB signaling pathway in both local intestinal and systemic compartments and promote the differentiation of regulatory T cells, thereby enhancing immune tolerance (Chen et al., 2024). Consequently, the loss of Faecalibacterium directly impairs endogenous anti-inflammatory capacity. Concurrently, the expansion of Gram-negative bacteria such as Shigella increases the release of pathogen-associated molecular patterns (PAMPs), particularly lipopolysaccharides, which compromise intestinal barrier function and translocate into the bloodstream. These PAMPs activate Toll-like receptors, triggering downstream activation of the NF-κB and NLRP3 inflammasome pathways, ultimately driving sustained elevation of pro-inflammatory cytokines, including IL-1β, IL-6, and CXCL2, in the serum (Cattaneo et al., 2017; Wang et al., 2025).

Ultimately, this persistent inflammatory state exerts a direct detrimental impact on skeletal muscle tissue. Elevated pro-inflammatory cytokines, including TNF-α and IL-6, activate key transcription factors such as NF-κB and STAT3, leading to significant upregulation of the muscle atrophy–associated E3 ubiquitin ligases MuRF1 and Atrogin-1, thereby promoting the ubiquitin-mediated degradation of structural proteins such as myosin heavy chain. Concurrently, these cytokines impair the insulin/IGF-1 signaling pathway by suppressing the Akt/mTOR/S6K1 signaling axis, a central regulator of protein synthesis (Pérez-Baos et al., 2018). The concomitant suppression of anabolic processes and enhancement of catabolic activity collectively drive progressive and sustained loss of muscle mass in older adults.

The production of key microbial metabolites is profoundly influenced by exogenous factors, particularly diet and pharmaceuticals. Dietary interventions, such as high-fiber diets that provide substrates for fermentation, or polyphenol-rich foods (e.g., berries, green tea) that are metabolized by specific bacteria, can significantly alter the metabolic output of the gut microbiota (Cardona et al., 2013; Sonnenburg and Sonnenburg, 2014). Conversely, drugs like antibiotics can drastically reduce the abundance of SCFA-producing bacteria, while metformin has been reported to increase SCFA levels (Wu et al., 2017). Regarding their stability and role, many of the most biologically active molecules are secondary metabolites. Primary metabolites like SCFAs (e.g., acetate, propionate, butyrate) are relatively stable within the gut lumen but are rapidly absorbed and utilized by host tissues, resulting in a relatively short systemic half-life. It is these secondary metabolites, transformed from dietary components by microbial enzymes, that often serve as the critical signaling molecules in the gut-muscle axis, directly modulating host inflammation, metabolism, and gene expression.

The gut microbiota modulates the neuroendocrine system via the gut-brain axis, constituting a sophisticated and intricately regulated biological pathway that influences skeletal muscle homeostasis. This bidirectional regulatory network exhibits marked sexual dimorphism, potentially contributing to sex-specific differences in susceptibility to sarcopenia and its progression.

On one hand, stress signals, such as elevated cortisol levels, can induce intestinal microbiota dysbiosis and compromise intestinal barrier integrity, thereby triggering systemic inflammatory responses via the LPS-TLR4 signaling pathway and ultimately activating molecular pathways associated with muscle atrophy (Lin et al., 2024). Evidence from mouse models with hypercortisolemia demonstrates a significant reduction in gut microbial diversity, characterized by a marked decrease in beneficial genera including Bifidobacterium and Lactobacillus, alongside a concomitant increase in potential pathobionts such as Escherichia coli and Streptococcus, further substantiating this mechanistic link (Nie et al., 2024). On the other hand, the gut microbiota exerts positive regulation over anabolic processes through multiple mechanisms: microbial metabolites, particularly SCFAs, have been shown to modulate the secretion of hypothalamic gonadotropin-releasing hormone (GnRH) in a remote manner, thereby enhancing pituitary-gonadal axis function and sustaining physiologically relevant levels of testosterone and estrogen, hormones critical for the maintenance of skeletal muscle mass (Judd et al., 1979; Qiu et al., 2007). Furthermore, Lactobacillus plantarum HL2 has been demonstrated to attenuate ovarian pathological alterations and restore normal secretion of luteinizing hormone, follicle-stimulating hormone, and testosterone, providing compelling experimental support for this regulatory axis (He et al., 2020). Emerging evidence indicates that specific members of the gut microbiota can modulate intestinal immune responses and promote the production of interleukin-13 (IL-13). Notably, enrichment of Prevotella copri has been shown to drive the polarization of naïve CD4+ T cells toward the T helper 2 (Th2) lineage within the gut mucosa, This specific skewing of the adaptive immune response leads to the production and elevation of interleukin-13 (IL-13) in the portal circulation. This cytokine is then transported to the liver via the portal vein, where it activates the IL-13 receptor (IL-13R)-JAK2-STAT6 signaling pathway, thereby triggering robust synthesis of insulin-like growth factor 1 (IGF-1) (Ma et al., 2024). This mechanistic insight directly connects intestinal immune modulation with systemic anabolic signaling essential for muscle growth.

It is noteworthy that the association between gut microbiota and muscle mass is markedly stronger in men than in women. For example, Park et al. (2022) reported in a large-scale population study that in males, the abundance of Roseburia faecis and Haemophilus parainfluenzae, taxa associated with butyrate production and improved insulin sensitivity, was significantly elevated, and gut microbial alpha diversity (assessed using the Shannon index) was positively correlated with skeletal muscle index (SMI). Asaoka et al. (2025) further confirmed that male patients with sarcopenia exhibited significantly reduced alpha diversity (Shannon index, p = 0.004), distinct beta diversity profiles, and markedly decreased abundance and detection rates of butyrate-producing taxa such as Eubacterium eligens and Fusicatenibacter. In contrast, no such significant alterations were observed in female sarcopenia cohorts. Notably, Park’s study, conducted in a middle-aged and younger male cohort (mean age: 45 years), already revealed a robust gut microbiota–muscle mass association, whereas Asaoka et al. (2025) identified an even stronger correlation in elderly men (mean age: 79 years), suggesting that age-related declines in testosterone levels and reductions in butyrate-producing bacteria may act synergistically, via modulation of hypothalamic-pituitary-adrenal (HPA) axis activity and insulin sensitivity, to promote muscle catabolism. This sexual dimorphism may be attributed to multiple underlying mechanisms: testosterone, the primary anabolic hormone in men, and its biosynthetic and signaling pathways, appear to be particularly sensitive to gut microbial status. With advancing age, the natural decline in circulating testosterone, when compounded by depletion of SCFA-producing genera (e.g., Roseburia faecis, Eubacterium), may exacerbate insulin resistance and low-grade systemic inflammation, thereby accelerating net skeletal muscle protein loss. In contrast, the female immune system typically demonstrates heightened innate inflammatory responsiveness, which may alter the functional weight of the microbiota-immune-IGF-1 regulatory axis or buffer its effects through estrogen-mediated protective mechanisms and other physiological compensatory pathways.

The bidirectional crosstalk between skeletal muscle and the intestine involves not only signal reception by skeletal muscle but also its active role as an endocrine organ, capable of releasing specific myokines to modulate intestinal function (Alpuim Costa et al., 2025). This section highlights the pivotal roles of exercise-induced myokines, such as irisin, myostatin (MSTN), and brain-derived neurotrophic factor (BDNF), in the “muscle-to-gut” retrograde signaling axis. These myokines contribute to the maintenance of intestinal homeostasis through coordinated regulation of intestinal barrier integrity, immune-inflammatory responses, and microbial community composition.

Irisin, an exercise-induced myokine, functions as a key mediator in the transmission of anti-inflammatory and protective signals from skeletal muscle to the intestine. Accumulating evidence indicates that Irisin exerts systemic beneficial effects on intestinal homeostasis. In preclinical models of ulcerative colitis and acute pancreatitis, administration of exogenous Irisin has been shown to significantly attenuate intestinal inflammation and tissue injury through inhibition of the MAPK signaling pathway and suppression of apoptotic processes (Huangfu et al., 2021; Ma et al., 2023; Ren et al., 2019). Notably, these protective effects are closely associated with remodeling of the gut microbiota composition, including enrichment of Deferribacteres and reduction of Bacteroides (Huangfu et al., 2021), suggesting that Irisin may mediate its therapeutic benefits via the “immune-microbiota” axis.

Myostatin, a key negative regulator of skeletal muscle growth, exerts significant influence on intestinal health. Studies using MSTN gene knockout pig models have demonstrated a notable phenotype: concomitant with muscle overgrowth, intestinal architecture is markedly improved, characterized by thickening of the muscularis layer of the intestinal wall and upregulation of tight junction proteins, including ZO-1 and Occludin. Importantly, the abundance of SCFA-producing bacteria is significantly increased in the gut (Luo et al., 2023). These findings strongly indicate that MSTN not only governs skeletal muscle development but also, through its absence, may indirectly enhance intestinal microecological balance and mucosal barrier integrity by modulating the secretion profile of myokines or systemic metabolic homeostasis.

Brain-derived neurotrophic factor elucidates the intricate interplay between the neuromuscular system and intestinal function. Beyond its well-documented role at the neuromuscular junction, BDNF originating from skeletal muscle is essential for preserving the integrity of the distal intestinal barrier. BDNF deficiency results in the disrupted expression of tight junction proteins in the colonic epithelium, including ZO-1, Occludin, and Claudin-1, leading to ultrastructural alterations and impaired barrier function, as demonstrated in BDNF knockout (BDNF−/−) mouse models (Li et al., 2018). Furthermore, accumulating evidence indicates that BDNF significantly contributes to the regulation of gut microbiota composition and the maintenance of intestinal homeostasis. Administration of BDNF in mice induces marked remodeling of the gut microbial architecture, characterized by increased alpha diversity, enrichment of beneficial SCFA-producing genera (e.g., Akkermansia, Faecalibacterium, and Lactobacillus), and reduced abundance of potential pathobionts such as Escherichia coli and Staphylococcus (Li et al., 2018). Collectively, these microbial shifts promote enhanced intestinal health. In summary, muscle-derived BDNF functions as a key endocrine mediator, critically involved in sustaining intestinal barrier integrity and modulating microbial community balance.

In summary, skeletal muscle actively participates in the regulation of intestinal function through the secretion of a diverse array of myogenic factors. Irisin primarily mediates anti-inflammatory responses and the modulation of the gut microbiota. The absence of MSTN is closely associated with enhanced intestinal barrier function and improved microbial metabolic profiles. BDNF, on the other hand, regulates the composition of the gut microbiota while directly reinforcing the intestinal physical barrier. Collectively, these factors construct a systemic network through which skeletal muscle influences intestinal health from multiple dimensions, including immune regulation, structural integrity, and microbial balance. This underscores the complexity and precision of the “top-down” regulatory signals originating from skeletal muscle within the gut-muscle axis. This mechanism not only deepens our understanding of the health benefits of exercise but also provides potential molecular targets for developing novel therapeutic strategies for intestinal or muscle-related diseases Figure 2.

Dysbiosis of the gut microbiota is a significant risk factor for the development of sarcopenia in elderly individuals. Consequently, modulating the composition of the gut microbiota has emerged as a critical strategy for mitigating sarcopenia. Studies have demonstrated that oral administration of Lactobacillus P62 (LP), Bifidobacterium P61 (BB), or a combination of both to aged mice can significantly enhance muscle strength and exercise capacity. Further research indicates that the primary mechanism of action involves activating the AKT signaling pathway, promoting muscle protein synthesis, inhibiting FOXO3a and NF-κB activity, reducing muscle catabolism and inflammatory responses, thereby alleviating age-related muscle atrophy (Baek et al., 2023). Additionally, a 16-week single-center randomized double-blind trial revealed that a probiotic supplement containing Bifidobacterium and Lactobacillus could increase muscle mass, strength, and activities of daily living in elderly men with age-related sarcopenia while concurrently reducing plasma LPS levels (Qaisar et al., 2024a).

Prebiotics, although indigestible by humans, are selectively utilized by intestinal microorganisms, thereby improving the composition and/or activity of the gut microbiota and exerting beneficial effects on human health. Research has shown that prebiotics can selectively stimulate the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus, while inhibiting the proliferation of harmful bacteria, thus optimizing the intestinal microecological balance. A study involving individuals over 65 years old with frailty syndrome found that continuous oral administration of a prebiotic composed of inulin and fructooligosaccharides for 13 weeks significantly increased grip strength and reduced fatigue scores (Yang et al., 2024a).

Synbiotics, which combine probiotics and prebiotics, have been shown to enhance muscle anabolic processes by regulating the balance of the gut microbiota, inhibiting the growth of harmful bacteria, reducing pro-inflammatory cytokine production, and promoting the generation of SCFAs. For example, a study using kimchi, a fermented product containing Lactobacillus plantarum and Lactobacillus mesenteroides, fed to mice with malignant adenomas, demonstrated decreased expression and serum levels of the pro-inflammatory IL-6, along with a significant increase in muscle mass by inhibiting the expression of Atrogin-1 and MuRF-1 genes and up-regulating the expression of mitofusin-2 and PGC-1α (An et al., 2019).

Although numerous studies have indicated the potential benefits of probiotics, prebiotics, and synbiotics in ameliorating sarcopenia-related parameters, the current body of clinical evidence remains markedly inconsistent. This heterogeneity may be attributed to several critical factors. First, the therapeutic effects of probiotics are highly strain-specific. Substantial differences in genetic profiles and functional metabolic activities exist among strains (Truong et al., 2017), implying that not all Lactobacillus or Bifidobacterium strains elicit comparable anti-sarcopenic effects. For example, certain strains, such as Lactobacillus plantarum TWK10, have demonstrated efficacy due to their distinct metabolic properties (Chen et al., 2016), whereas others may lack beneficial activity. Second, dosage and treatment duration represent key determinants of intervention outcomes. The wide variability in administered doses (e.g., 10^∧9–10^∧11 CFU/day) and intervention periods (ranging from 8 to 24 weeks) across existing studies may partly explain conflicting results; insufficient dosing or inadequate duration may fail to induce sustained modulation of the gut microbiota (Prokopidis et al., 2023). Third, host-specific factors play a pivotal role. Seminal research has established that the composition and baseline stability of an individual’s gut microbiome are fundamental to the successful engraftment and functional activity of probiotic strains (Zmora et al., 2018). Moreover, elderly individuals with sarcopenia frequently use multiple medications—including antibiotics and proton pump inhibitors—and experience age-related immune alterations, both of which can perturb the intestinal microenvironment. These factors may impair probiotic colonization and functionality and, in certain contexts (e.g., following antibiotic exposure), delay the restoration of indigenous microbial communities (Suez et al., 2018).

In summary, future sarcopenia research must move toward precision microbiome interventions through the development of personalized regimens to ensure consistent and reliable therapeutic outcomes.

Fecal Microbiota Transplantation (FMT), as a therapeutic approach that enhances host health by modulating the gut microbiota, has shown promise in preliminary research in addressing sarcopenia in elderly populations. In a preclinical study, fecal samples from healthy young mice were collected and processed into a microbiota suspension suitable for transplantation. This suspension was subsequently administered to the intestines of aged mice. The results indicated that the FMT-treated elderly mice exhibited significantly improved performance in grip strength and exercise endurance tests compared to the control group. This improvement may be attributed to the significant increase in jejunal microbiota α-diversity induced by FMT, leading to the enrichment of bacterial genera such as Pseudoscardovia, Solobacterium, Shuttleworthia, and Pseudoraminibacter, and the modulation of metabolic pathways for carbohydrates, amino acids, and vitamin (Mo et al., 2023). Preliminary clinical evidence suggests that in older adults (≥60 years) with sarcopenia, a regimen of FMT delivered via a nasojejunal tube, coupled with resistance training, may be associated with improved outcomes. Reported benefits in initial studies include an approximate 15% increase in complete remission rates, a rise in the appendicular skeletal muscle index of around 0.1 kg/m², and reductions in serum inflammatory markers such as IL-6, TNF-α, and CRP. Further investigations have revealed that FMT increases the α-diversity of the intestinal microbiota and elevates the abundance of butyrate-producing genera, including Faecalibacterium, Roseburia, Dorea, Coprococcus, Blautia, and Agathobacter. Conversely, the abundances of Veillonella and Erysipelotrichaceae, both of which exhibit a strong positive correlation with TNF-α (r = 0.963), are reduced (Yang et al., 2025). These findings suggest that the therapeutic mechanism may be closely associated with the remodeling of the “butyrate-producing bacteria–short-chain fatty acids–anti-inflammatory–intestinal barrier” axis. Age-related dysbiosis triggers a pathological cascade from the gut to muscle: it compromises the intestinal barrier (reducing goblet cells, Muc-2, and tight junction proteins), leading to LPS translocation, NLRP3-mediated chronic inflammation, and ultimately, suppression of muscle protein synthesis and sarcopenia (Mo et al., 2023). Conversely, FMT from young donors interrupts this cascade by reconstructing a beneficial microbiota (e.g., increasing Akkermansia and Lactobacillus). This intervention concurrently restores barrier integrity, reduces systemic LPS and inflammation, and ameliorates muscle mitochondrial decline, thereby preserving muscle function (Diao et al., 2018; Mo et al., 2023).

However, it is crucial to interpret these encouraging findings with caution, as the current body of evidence is constrained by several important limitations. Many clinical studies, including the aforementioned preliminary trials, are characterized by small sample sizes and short follow-up durations, which limit the statistical power and the ability to assess the long-term efficacy and stability of FMT interventions. Furthermore, FMT is not without potential risks. Procedural concerns and the possibility of transferring pathogenic or antibiotic-resistant organisms, as evidenced by severe adverse events in immunocompromised patients (DeFilipp et al., 2019), underscore the necessity for rigorous donor screening and safety monitoring.

It is important to recognize that the complete prevention or effective management of long-term dysbiosis recurrence following fecal microbiota transplantation (FMT) continues to represent a significant unmet clinical challenge. FMT fundamentally functions as a single-event “ecological transplantation”; however, the stability of the transplanted microbial community is frequently compromised by ongoing host-specific factors, dietary patterns, medication use, and environmental influences. Furthermore, the limited colonization capacity and relatively short half-life of transplanted bacterial strains further hinder the long-term persistence of the introduced microbiota. In addition, prolonged and repeated administration of whole-community FMT may pose a risk of transmitting antibiotic-resistant pathogens or other harmful microorganisms. Therefore, addressing this challenge extends beyond the scope of individual studies and represents a priority area that requires sustained interdisciplinary research and collaborative efforts across the field.

Recent studies suggest that dietary nutrients specifically targeting skeletal muscle, consisting of hydroxymethyl butyrate (HMB), carnosine, magnesium, butyrate, and lactoferrin, may significantly enhance muscle strength, increase muscle mass, and improve the Short Physical Performance Battery (SPPB) score in elderly patients suffering from sarcopenia. Furthermore, these dietary supplements have been shown to reduce plasma levels of CRP and TNF-α, both of which are established markers of inflammation, as well as zonulin, an indicator of intestinal permeability. The reduction in these biomarkers suggests that the dietary supplement possesses anti-inflammatory properties and may contribute to the restoration of intestinal barrier function (Rondanelli et al., 2024). Research has indicated that HMB, a metabolite derived from leucine, enhances muscle mass and strength by promoting protein synthesis and facilitating energy metabolism (Martínez-Arnau et al., 2020). In addition, carnosine is composed of β-alanine and L-histidine, and supplementation of β-alanine can directly increase the carnosine reserve in skeletal muscle and enhancing its mass and function (Furst et al., 2018). In addition, butyrate and lactoferrin in this dietary supplement have been shown to inhibit inflammatory responses by regulating the NF-kB signaling pathway (Frioni et al., 2014). Recent studies have also found that butyrate reduces muscle atrophy by repairing the neuromuscular junction (Qaisar et al., 2024b).

Another randomized double-blind controlled trial showed that, compared with the placebo group with the same caloric and flavor, the group of special medical use nutrition supplement consisting of omega-3 fatty acids, leucine and probiotics Lactobacillus paracasei PS23 significantly improved Tinetti score, SPPB score and grip strength after 2 months (Rondanelli et al., 2022). This special medical use nutrition supplement also employs a multi-target therapeutic strategy to tackle age-related sarcopenia. Notably, older adults with sarcopenia typically consume lower levels of omega-3 polyunsaturated fatty acids, which promote muscle synthesis, and their intake is positively associated with secondary outcomes such as SF-36 psychological scores and Sarcopenia Quality of Life Questionnaire (SarQoL). Therefore, omega-3 fatty acids are regarded as an important potential target for the treatment of muscle atrophy, and the daily supplementation of 0.7g–3.36 g of omega-3 fatty acids is currently recommended for the elderly (Dupont et al., 2023; Rondanelli et al., 2022).

Exercise intervention is a cornerstone strategy in the management of sarcopenia, particularly resistance training and aerobic exercise, which have been shown to significantly enhance muscle mass and function in patients with sarcopenia (Millan-Domingo et al., 2024). An 8-week randomized controlled trial examined the effects of kettlebell training on elderly female sarcopenia patients. The results demonstrated that kettlebell training markedly improved muscle mass, grip strength, and lung function, while reducing levels of the chronic low-grade inflammation marker CRP. These improvements persisted for up to 4 weeks post-training cessation (Chen et al., 2018). Another study involving sarcopenic patients aged 80–99 years found that 12 weeks of combined resistance and balance training significantly increased grip strength and back muscle strength (Liang et al., 2020).

Exercise has been shown to directly enhance muscle mass, strength, and physical fitness in sarcopenia patients by modulating the gut microbiota. Exercise training alters the composition of the gut microbiota, reducing the abundance of Clostridium bacteria, especially Blautia bacteria that promote the release of pro-inflammatory cytokine TNF-α. Simultaneously, exercise increases the abundance of Bacteroidetes, Actinobacteria, and Bifidobacterium species with anti-inflammatory properties (Xie and Huang, 2024). Evidence from plasma inflammatory marker assessments indicates that exercise reduces levels of LBP, TNF-α, and CRP through its regulatory effects on the gut microbiota (Motiani et al., 2020). Studies examining the impact of different exercise intensities on gut microbiota and muscle function suggest that long-term high-intensity training may alter microbial composition, specifically decreasing bacteria associated with SCFAs production while increasing those involved in inflammatory processes. Consequently, prolonged high-intensity exercise may increase intestinal permeability and elevate plasma LPS levels, triggering inflammatory responses within skeletal muscles and impacting their function. In contrast, short-term moderate-intensity training appears beneficial for enhancing SCFA-producing bacterial populations and improving physical activity capacity; however, this positive effect tends to diminish following training cessation (Gao and Zhang, 2024). Therefore, it is recommended to maintain a regimen of long-term moderate-intensity exercise to better regulate gut microbiota, reduce muscle inflammation, improve mitochondrial function, and ultimately enhance muscle mass and strength, as well as overall physical function Table 2.