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 Ca<sup>2+</sup>-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca<sup>2+</sup>) storage and dysregulated Ca<sup>2+</sup> 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.
Authors
- Holly Van Remmen (ORCID: https://orcid.org/0000-0003-0883-0642)
- Lisa M. Hartnell (ORCID: https://orcid.org/0000-0001-8553-392X)
- Axel R. Concepcion (ORCID: https://orcid.org/0000-0003-2971-3488)
- Pura Muñoz‐Cánoves (ORCID: https://orcid.org/0000-0002-7533-9047)
- Julie A. Reisz (ORCID: https://orcid.org/0000-0002-7296-4963)
- Luisa Coletto
- Rizwan Qaisar (ORCID: https://orcid.org/0000-0001-8485-7172)
- Angelo D’Alessandro (ORCID: https://orcid.org/0000-0002-2258-6490)
- Luigi Ferrucci (ORCID: https://orcid.org/0000-0002-6273-1613)
- Nirad Banskota (ORCID: https://orcid.org/0009-0000-5511-8346)
- Ana María Cuervo (ORCID: https://orcid.org/0000-0002-0771-700X)
- Stefano Donegà (ORCID: https://orcid.org/0000-0003-0669-1618)
- Ignacio Ramírez‐Pardo (ORCID: https://orcid.org/0000-0003-4873-7274)
- Olaya Santiago‐Fernández (ORCID: https://orcid.org/0000-0002-5933-3104)
- Susmita Kaushik (ORCID: https://orcid.org/0000-0002-6096-5387)
- Bumsoo Ahn (ORCID: https://orcid.org/0000-0002-2743-7099)
- Inmaculada Tasset (ORCID: https://orcid.org/0000-0003-0730-6750)
- Kristen L. Lindenau (ORCID: https://orcid.org/0000-0001-6145-5322)
- Michael T Kinter (ORCID: https://orcid.org/0000-0001-7409-8918)
- Adrián Macho‐González (ORCID: https://orcid.org/0000-0001-7644-1759)
- Gavin Pharaoh (ORCID: https://orcid.org/0000-0001-7221-7346)
- Rabia R. Khawaja (ORCID: https://orcid.org/0000-0003-3907-988X)
- Stefan Feske (ORCID: https://orcid.org/0000-0001-5431-8178)
- Ceereena Ubaida‐Mohien (ORCID: https://orcid.org/0000-0002-4301-4758)
- Antonio Díaz (ORCID: https://orcid.org/0000-0001-7871-0828)
- Bhakti Chavda
- Aiara Gazteluiturri
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Fleet Science Center (US)
- National Institutes of Health (US)
- Albert Einstein College of Medicine (US)
- Universitat Pompeu Fabra (ES)
- Spanish National Centre for Cardiovascular Research (ES)
- Oklahoma Medical Research Foundation (US)
- University of Chicago (US)
- Oklahoma City VA Medical Center (US)
- Institute on Aging (US)
- National Institute on Aging (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Córdoba (ES)
- New York University (US)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1038/s42255-025-01412-9
- Citations
- 3
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 4.06