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<p>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.</p>

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Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月3日

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  • Olaya Santiago-Fernández,
  • Luisa Coletto,
  • Inmaculada Tasset,
  • Susmita Kaushik,
  • Axel R. Concepcion,
  • Rizwan Qaisar,
  • Adrián Macho-González,
  • Kristen Lindenau,
  • Antonio Diaz,
  • Rabia R. Khawaja,
  • Stefano Donega,
  • Nirad Banskota,
  • Ceereena Ubaida-Mohien,
  • Gavin Pharaoh,
  • Bumsoo Ahn,
  • Lisa M. Hartnell,
  • Ignacio Ramírez-Pardo,
  • Bhakti Chavda,
  • Aiara Gazteluiturri,
  • Michael Kinter,
  • Luigi Ferrucci,
  • Julie A. Reisz,
  • Angelo D’Alessandro,
  • Holly Van Remmen,
  • Pura Muñoz-Cánoves,
  • Stefan Feske,
  • Ana Maria Cuervo

摘要

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.