Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological changes. Mitochondrial dysfunction can lead to skeletal muscle atrophy, and its molecular mechanism leading to skeletal muscle atrophy is complex. Understanding the pathogenesis of mitochondrial dysfunction is useful for the prevention and treatment of skeletal muscle atrophy, and finding drugs and methods to target and modulate mitochondrial function are urgent tasks in the prevention and treatment of skeletal muscle atrophy. In this review, we first discussed the roles of normal mitochondria in skeletal muscle. Importantly, we described the effect of mitochondrial dysfunction on skeletal muscle atrophy and the molecular mechanisms involved. Furthermore, the regulatory roles of different signaling pathways (AMPK-SIRT1-PGC-1α, IGF-1-PI3K-Akt-mTOR, FoxOs, JAK-STAT3, TGF-β-Smad2/3 and NF-κB pathways, etc.) and the roles of mitochondrial factors were investigated in mitochondrial dysfunction. Next, we analyzed the manifestations of mitochondrial dysfunction in muscle atrophy caused by different diseases. Finally, we summarized the preventive and therapeutic effects of targeted regulation of mitochondrial function on skeletal muscle atrophy, including drug therapy, exercise and diet, gene therapy, stem cell therapy and physical therapy. This review is of great significance for the holistic understanding of the important role of mitochondria in skeletal muscle, which is helpful for researchers to further understanding the molecular regulatory mechanism of skeletal muscle atrophy, and has an important inspiring role for the development of therapeutic strategies for muscle atrophy targeting mitochondria in the future.

Various diseases can cause skeletal muscle atrophy, usually accompanied by inflammation, mitochondrial dysfunction, apoptosis, decreased protein synthesis, and enhanced proteolysis. The underlying mechanism of inflammation in skeletal muscle atrophy is extremely complex and has not been fully elucidated, thus hindering the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy. In this review, we elaborate on protein degradation pathways, including the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), the calpain and caspase pathways, the insulin growth factor 1/Akt protein synthesis pathway, myostatin, and muscle satellite cells, in the process of muscle atrophy. Under an inflammatory environment, various pro-inflammatory cytokines directly act on nuclear factor-κB, p38MAPK, and JAK/STAT pathways through the corresponding receptors, and then are involved in muscle atrophy. Inflammation can also indirectly trigger skeletal muscle atrophy by changing the metabolic state of other tissues or cells. This paper explores the changes in the hypothalamic-pituitary-adrenal axis and fat metabolism under inflammatory conditions as well as their effects on skeletal muscle. Moreover, this paper also reviews various signaling pathways related to muscle atrophy under inflammatory conditions, such as cachexia, sepsis, type 2 diabetes mellitus, obesity, chronic obstructive pulmonary disease, chronic kidney disease, and nerve injury. Finally, this paper summarizes anti-amyotrophic drugs and their therapeutic targets for inflammation in recent years. Overall, inflammation is a key factor causing skeletal muscle atrophy, and anti-inflammation might be an effective strategy for the treatment of skeletal muscle atrophy. Various inflammatory factors and their downstream pathways are considered promising targets for the treatment and prevention of skeletal muscle atrophy.

Background: The AMPK/SIRT1/PGC‐1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target. Methods: We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms—including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease—to dissect its tissue‐specific pathophysiological impacts. Results: The AMPK/SIRT1/PGC‐1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC‐1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease‐specific mechanisms: promoting Aβ production via BACE1/γ‐secretase in Alzheimer's; impairing α‐synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF‐β/Smad3 signaling. Conclusions: The AMPK/SIRT1/PGC‐1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies—including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)—offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue‐specific regulatory mechanisms, such as AMPK isoform diversity and PGC‐1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders.

The maintenance of muscle homeostasis is vital for life and health. Skeletal muscle atrophy not only seriously reduces people’s quality of life and increases morbidity and mortality, but also causes a huge socioeconomic burden. To date, no effective treatment has been developed for skeletal muscle atrophy owing to an incomplete understanding of its molecular mechanisms. Exercise therapy is the most effective treatment for skeletal muscle atrophy. Unfortunately, it is not suitable for all patients, such as fractured patients and bedridden patients with nerve damage. Therefore, understanding the molecular mechanism of skeletal muscle atrophy is crucial for developing new therapies for skeletal muscle atrophy. In this review, PubMed was systematically screened for articles that appeared in the past 5 years about potential therapeutic strategies for skeletal muscle atrophy. Herein, we summarize the roles of inflammation, oxidative stress, ubiquitin-proteasome system, autophagic-lysosomal pathway, caspases, and calpains in skeletal muscle atrophy and systematically expound the potential drug targets and therapeutic progress against skeletal muscle atrophy. This review focuses on current treatments and strategies for skeletal muscle atrophy, including drug treatment (active substances of traditional Chinese medicine, chemical drugs, antioxidants, enzyme and enzyme inhibitors, hormone drugs, etc.), gene therapy, stem cell and exosome therapy (muscle-derived stem cells, non-myogenic stem cells, and exosomes), cytokine therapy, physical therapy (electroacupuncture, electrical stimulation, optogenetic technology, heat therapy, and low-level laser therapy), nutrition support (protein, essential amino acids, creatine, β-hydroxy-β-methylbutyrate, and vitamin D), and other therapies (biomaterial adjuvant therapy, intestinal microbial regulation, and oxygen supplementation). Considering many treatments have been developed for skeletal muscle atrophy, we propose a combination of proper treatments for individual needs, which may yield better treatment outcomes.

Background: The molecular mechanisms underlying denervated skeletal muscle atrophy with concomitant muscle mass loss have not been fully elucidated. Therefore, this study aimed to attain a deeper understanding of the molecular mechanisms underlying denervated skeletal muscle atrophy as a critical step to developing targeted therapy and retarding the concomitant loss of skeletal muscle mass. Methods: We employed microarray analysis to reveal the potential molecular mechanisms underlying denervated skeletal muscle atrophy. We used in vitro and in vivo atrophy models to explore the roles of the interleukin 6 (IL-6), Janus kinase (JAK), and signal transducers and activators of transcription 3 (STAT3) in muscle atrophy. Results: In this study, microarray analysis of the differentially expressed genes demonstrated that inflammation-related cytokines were markedly triggered and IL-6/JAK/STAT3 signaling pathway was strongly activated during denervated skeletal muscle atrophy. The high level of IL-6 enhanced C2C12 myotube atrophy through the activation of JAK/STAT3, while inhibiting JAK/STAT3 pathway by ruxolitinib (a JAK1/2 inhibitor) or C188-9 (a STAT3 inhibitor) significantly attenuated C2C12 myotube atrophy induced by IL-6. Pharmacological blocking of IL-6 by tocilizumab (antibody against IL-6 receptor) and pharmacological/genetic inhibition of JAK/STAT3 pathway by ruxolitinib/C188-9 (JAK/STAT3 inhibitor) and STAT3 short hairpin RNA (shRNA) lentivirus in tibialis anterior muscles could suppress muscle atrophy and inhibit mitophagy, and was accompanied by the decreased expression of atrophic genes (MuRF1 and MAFbx) and autophagy-related genes (PINK1, BNIP3, Beclin 1, ATG7, and LC3B). Conclusions: Taken together, the results suggest that IL-6/JAK/STAT3 pathway may be a principal mediator in denervated skeletal muscle atrophy, meaning targeted therapy against IL-6/JAK/STAT3 pathway might have potential as a therapeutic strategy for prevention of skeletal muscle atrophy.