Yuhao Wang

Skeletal muscle aging is a conserved biological process characterized by progressive declines in muscle mass, strength, regenerative capacity, and metabolic adaptability, contributing to impaired mobility, frailty and age-related diseases. Beyond its canonical role in locomotion, skeletal muscle functions as an endocrine and metabolic organ that actively regulates organismal aging through myokines, metabolites, extracellular vesicles, thermogenic activity, and dynamic communication with distant organs. In this review, we summarize the intrinsic mechanisms driving skeletal muscle aging, including protein turnover imbalance and anabolic resistance, myosteatosis, denervation and motor unit loss, and cellular composition remodeling. We also discuss how aging skeletal muscle influences systemic aging through bidirectional interactions with metabolic organs, brain, cardiovascular system, and bone via endocrine signaling and interorgan communication. Finally, we highlight emerging interventions targeting skeletal muscle aging, including exercise, nutritional strategies, pharmacological approaches, and other novel therapies. Understanding skeletal muscle as both a target and regulator of systemic aging provides a framework for developing strategies to promote healthy aging and reduce the burden of age-associated diseases.

Obesity disrupts skeletal muscle metabolism through insulin resistance, oxidative stress, and ectopic fat deposition, yet transcriptomic findings across individual studies remain inconsistent. We performed a meta-analysis of four independent RNA sequencing (RNA-seq) studies of human vastus lateralis muscle, comparing 29 individuals with obesity (body mass index (BMI) ≥ 30 kg/m²) and 23 with normal weight. Differential expression was analyzed using DESeq2, with age and sex included as covariates in studies where individual-level data were available. Study-level results were integrated using the direction-aware inverse normal method (weighted Stouffer). Between-study heterogeneity was assessed by gene-level I² statistics derived from random-effects meta-analysis of log₂ fold changes. Functional annotation was performed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The weighted Stouffer method identified 2136 differentially expressed genes (DEGs) (adjusted p < 0.05), comprising 1028 upregulated and 1108 downregulated genes, of which 674 (31.6%) were detected only through the meta-analysis. Three genes—PHLDA3 (down), CNKSR2 (down), and SFRP4 (up)—were significant in every individual study and in the combined analysis. Downregulated DEGs were enriched in cytoplasmic translation, ribosomal structure, and oxidative phosphorylation, whereas upregulated DEGs were associated with extracellular matrix organization and the focal adhesion pathway. This RNA-seq meta-analysis of skeletal muscle in obesity identifies robust DEGs and dysregulated pathways, providing candidate targets for future mechanistic and translational research.

Obesity leads to a chronic inflammatory state throughout the body, with increased infiltration of immune cells and inflammatory factors in skeletal muscle tissue, and, at the same time, the level of intracellular mitochondrial oxidative stress rises. Meanwhile, obesity is closely related to the development of skeletal muscle fibrosis and can affect the metabolic function of skeletal muscle, triggering metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D). However, whether there is a mutual regulatory effect between the two pathological states of inflammation and fibrosis in obese skeletal muscle and the specific molecular mechanisms have not been fully clarified. This review focuses on the pathological changes of skeletal muscle inflammation and fibrosis induced by obesity, covering the metabolic changes it causes, such as lipid deposition, mitochondrial dysfunction, and dysregulation of inflammatory factors, aiming to reveal the intricate connections between the two. In terms of intervention strategies, aerobic exercise, dietary modification, and pharmacotherapy can improve skeletal muscle inflammation and fibrosis. This article provides insight into the important roles of inflammation and fibrosis in the treatment of obesity and the management of skeletal muscle diseases, aiming to provide new ideas for the diagnosis and treatment of metabolic diseases such as obesity and IR.