Nat Aging. 2026 Sep 29.
Fabian Finger,
Mikkel Frost,
Shinya Watanabe,
Tao Ma,
Taewook Kang,
Dipsikha Biswas,
Ruben Zapata-Perez,
Vincent Anton,
Lucile Dollet,
Lasse K Markussen,
Nanami Senoo,
Iuliia Karavaeva,
Astrid Linde Basse,
Oksana Dmytriyeva,
Tara TeSlaa,
Jesper F Havelund,
Amy M Ehrlich,
Marta Moreno-Torres,
Caio Yogi Yonamine,
Nicoline R Andersen,
Ida Blom,
Francisco Garcia-Carrizo,
Piyarat Siripoksup,
Magnus Asping,
Thomas S Nielsen,
Marcus Nygård,
Anders B Klein,
Andrey Tvardovskiy,
Trine S Nicolaisen,
Carlos Durantez-Fernández,
Klaus Qvortrup,
Clara Prats,
Joshua D Rabinowitz,
Christoffer Clemmensen,
Lykke Sylow,
Juleen R Zierath,
Jonas T Treebak,
Tim J Schulz,
Trisha J Grevengoed,
Steven M Claypool,
Julien Prudent,
Rob C I Wüst,
Susanne Mandrup,
Riekelt H Houtkooper,
Kei Sakamoto,
Nils J Færgeman,
Martin R Larsen,
Katsuhiko Funai,
Steen Larsen,
Zachary Gerhart-Hines.
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.