Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ

Abstract Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 ( Crls1 ) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.

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Publication Details

Journal
Nature Aging
Published
2026-09-29
DOI
https://doi.org/10.1038/s43587-026-01227-7
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
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article

Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ

Juleen Rae Zierath, Vincent Anton, Fabian Finger, Amy M. Ehrlich et al.
Nature Aging
Mitochondrial Function and Pathology
article

Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ

Juleen Rae Zierath, Vincent Anton, Fabian Finger, Amy M. Ehrlich, Caio Yogi Yonamine, Kei Sakamoto, Riekelt H. Houtkooper, Trisha Jean Grevengoed, Anders Bue Klein, Mikkel Frost, Lasse Kruse Markussen, Lucile Dollet, Thomas S. Nielsen, Piyarat Siripoksup, Jonas T. Treebak, Oksana Dmytriyeva, Taewook Kang, Astrid Linde Basse, Susanne Mandrup, Marta Moreno‐Torres, Clara Prats, Nils Joakim Færgeman, Nanami Senoo, Tara A. TeSlaa, Ida Blom, Rob C. I. Wüst, Iuliia E. Karavaeva, Rubén Zapata‐Pérez, Katsuhiko Funai, Joshua D. Rabinowitz, Steen Larsen, Lykke Sylow, Julien Prudent, Marcus Nygård, Dipsikha Biswas, Steven Michael Claypool, Klaus Qvortrup, Zachary Gerhart‐Hines, Shinya Watanabe, Tim Julius Schulz, Nicoline R. Andersen, Trine S. Nicolaisen, Magnus Asping, Andrey Tvardovskiy, Jesper Foged Havelund, Christoffer Clemmensen, Francisco García‐Carrizo, Tao Ma, Martin R. Larsen
article en

Abstract

Abstract Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 ( Crls1 ) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.

Nature Aging
University of Copenhagen (DK), Johns Hopkins University (US), Medical University of Białystok (PL), Universitat de València (ES), University of California, Los Angeles (US), University of Potsdam (DE), University of Southern Denmark (DK), Princeton University (US), University of Utah (US), University of Cambridge (GB), Johns Hopkins Medicine (US), Frederiksberg Hospital (DK), Instituto de Salud Carlos III (ES), Karolinska Institutet (SE), Helmholtz Zentrum München (DE), Amsterdam Neuroscience (NL), Centro de Investigación Biomédica en Red (ES), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Ludwig Cancer Research (US), German Center for Diabetes Research (DE), German Institute of Human Nutrition (DE), Instituto de Investigación Sanitaria La Fe (ES), Novo Nordisk Foundation Center for Basic Metabolic Research, Amsterdam Movement Sciences (NL), Institute of Functional Epigenetics (DE), Universidad Católica de Murcia (ES), MRC Mitochondrial Biology Unit (GB), Vrije Universiteit Amsterdam (NL), University of Amsterdam (NL)
Openalex Percentile: Top 19%
Mitochondrial Function and Pathology
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