A number of distinct cellular processes are labeled as forms of autophagy. These are ways in which a cell identifies unwanted structures and molecules, conveys those unwanted structures and molecules to a lysosome, and there breaks down the unwanted structures and molecules into raw materials. Autophagy is necessary for cell function, and has attracted attention in the aging research space for a number of reasons. Firstly the efficiency of autophagy appears to decline with age, secondly a number of ways to alter metabolism to modestly slow aging, such as calorie restriction and mTOR inhibition, appear to primarily function via increased efficiency of autophagy, and thirdly a few strategies to directly and selectively improve the efficiency of autophagy, such as LAMP2A upregulation, have also been shown to slow aging.
Today the focus is on chaperone mediated autophagy, in which unwanted proteins bind to a chaperone protein such as HSC70 that in turn binds to features such as LAMP2A on the surface of a lysosome, allowing the unwanted protein to be engulfed and then broken down. A pair of recently published papers from a team that has been working on LAMP2A for twenty years or so caught my attention. The work implicates an age-related decline in the efficiency of chaperone mediated autophagy in the aging of muscle tissue. The researchers show that maintaining efficient chaperone mediated autophagy in later life, achieved via upregulation of LAMP2A in a genetically engineered mouse lineage, can slow the age-related loss of muscle mass and strength. This approach likely works via helping to maintain muscle stem cell function into later life.
Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy
Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise, and tissue repair, but declines in ageing and obesity.
Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.
Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age
Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration.
Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.
