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Finger, F.* ; Frost, M.* ; Watanabe, S.* ; Ma, T.* ; Kang, T.* ; Biswas, D.* ; Perez, R.Z.* ; Anton, V.* ; Dollet, L.* ; Markussen, L.K.* ; Senoo, N.* ; Karavaeva, I.E.* ; Basse, A.L.* ; Dmytriyeva, O.* ; TeSlaa, T.A.* ; Havelund, J.F.* ; Ehrlich, A.M.* ; Moreno‐Torres, M.* ; Yonamine, C.Y.* ; Andersen, N.R.* ; Blom, I.* ; García‐Carrizo, F.* ; Siripoksup, P.* ; Asping, M.* ; Nielsen, T.S.* ; Nygård, M.* ; Klein, A.B.* ; Tvardovskiy, A. ; Nicolaisen, T.S.* ; Nygård, M.* ; Qvortrup, K.* ; Prats, C.* ; Rabinowitz, J.D.* ; Clemmensen, C.* ; Sylow, L.* ; Zierath, J.R.* ; Treebak, J.T.* ; Schulz, T..J.* ; Grevengoed, T.J.* ; Claypool, S.M.* ; Prudent, J.* ; Wüst, R.C.I.* ; Mandrup, S.* ; Houtkooper, R.H.* ; Sakamoto, K.* ; Færgeman, N.J.* ; Larsen, M.R.* ; Funai, K.* ; Larsen, S.* ; Gerhart‐Hines, Z.*

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

Nature Aging, DOI: 10.1038/s43587-026-01227-7 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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 type Article: Journal article
Document type Scientific Article
Keywords Skeletal-muscle; Insulin-resistance; Obesity; Oxygen; Fgf21; Ros; Metabolism; Biomarkers; Sarcopenia; Deletion
ISSN (print) / ISBN 2662-8465
e-ISSN 2662-8465
Journal Nature Aging
Publisher Nature Publishing Group
Publishing Place The Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institiute of Functional Epigenetics (IFE)
Grants RCUK | Medical Research Council (MRC)
U.S. Department of Health & Human Services | National Institutes of Health (NIH)
Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)
Lundbeckfonden (Lundbeck Foundation)
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)