Muscle Autophagy Pathway Declines With Age, Causing Progressive Weakness

Skeletal muscle maintains its integrity through a precise balance between protein synthesis and degradation. While macroautophagy in muscle is well studied, the role of chaperone-mediated autophagy (CMA)—a selective lysosomal degradation pathway—has remained largely unexplored in this tissue. This paper provides the first comprehensive dissection of CMA's role in skeletal muscle physiology and aging.

CMA operates through a chaperone-receptor axis: the cytosolic chaperone HSC70 recognizes proteins bearing a KFERQ-like pentapeptide motif and delivers them to the lysosomal receptor LAMP2A for translocation and degradation. The researchers first established that CMA is dynamically regulated in skeletal muscle—it is upregulated during nutrient deprivation (starvation), acute exercise, and tissue repair, but is markedly reduced in both aged and obese mice. Importantly, CMA downregulation was confirmed in aging human skeletal muscle biopsies, validating the translational relevance of the findings.

To determine the causal role of CMA, the team generated a muscle-specific LAMP2A knockout mouse (HSA-Cre:L2A fl/fl), which progressively develops a myopathic phenotype. These animals exhibit reduced grip strength and muscle force, myofiber degeneration, and histological features reminiscent of human myopathies. Comparative proteomics between knockout and control muscles revealed substantial CMA-dependent changes in the mitochondrial proteome, suggesting that CMA contributes to mitochondrial quality control in muscle cells.

A key mechanistic discovery was the identification of SERCA (sarcoplasmic-endoplasmic reticulum Ca²⁺-ATPase) as a bona fide CMA substrate. SERCA is the primary calcium pump responsible for sequestering Ca²⁺ back into the sarcoplasmic reticulum following muscle contraction. In CMA-deficient muscle, SERCA turnover is impaired, leading to abnormal calcium storage and dysregulated calcium dynamics—a likely driver of the contractile dysfunction and fiber damage observed. This finding links CMA directly to excitation-contraction coupling, a fundamental muscle physiology process.

Perhaps most therapeutically significant, the study showed that genetic upregulation of LAMP2A specifically in aged mouse skeletal muscle partially rescues age-associated muscle decline—improving fiber integrity and functional parameters. This proof-of-concept result suggests that pharmacological or gene-based CMA enhancement could be a viable strategy to combat sarcopenia and age-related myopathies. The work establishes CMA as an essential regulator of skeletal muscle homeostasis and identifies its decline as a mechanistic contributor to muscle aging.