Declining was linked to skeletal muscle dysfunction, while boosting CMA partly improved ageing muscle phenotypes in mice.
Evidence
This mechanistic study combined muscle-specific CMA-deficient mice, proteomic analyses, ageing and obesity contexts, old-mouse CMA upregulation, and confirmation of age-related CMA downregulation in human skeletal muscle.
Caveat
Most functional and rescue evidence comes from mouse models, so the human data support age-related CMA decline but not clinical benefit from CMA upregulation.
Simplified
(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 , 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 Ca-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca) storage and dysregulated Cadynamics. 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. 2+ 2+ 2+
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Competing interests: A.M.C. was a co-founder and scientific advisor for the autophagy programme at Life Biosciences during part of this project. S.F. is a scientific co-founder, advisor and shareholder for CalciMedica. These activities were outside the scope of the current study. P.M.C. is a current employee and I.R.P. was a former employee of Altos Labs. Financial support was not provided for this work, and no data were shared with Life Biosciences, CalciMedica or Altos Labs. The remaining authors declare no competing interests.
