MechanismsAnimals

Cardiolipin decline drives muscle fiber shifts in mice

Deleting cardiolipin synthase in young mice induced age-like fiber shifts, while restoring its expression reversed atrophy and rescued premature mortality.

Figure 1 from Nature Aging — Figure 1Finger et al.

Nature Aging2 Oct 2026, 23:17 BST

In mice and human skeletal muscle, researchers investigated how the mitochondrial membrane lipid cardiolipin coordinates age-related fiber remodeling. By deleting cardiolipin synthase 1 in young mice to mimic the loss of muscle cardiolipin seen in aging, the authors reproduced key aging hallmarks, including a shift from glycolytic to oxidative fibers. This transition was mediated by mitochondria-to-nucleus signaling through the nuclear receptor estrogen-related receptor γ, which drove reactive oxygen species-sensitive glucose uptake and glycolytic rerouting to sustain antioxidant defenses. Restoring cardiolipin synthase 1 expression in adult knockout mice reestablished cardiolipin levels, initiated the reversal of muscle atrophy, and fully rescued premature mortality.

Why it matters

The findings describe a cell-autonomous lipid pathway that connects mitochondrial dysfunction to fiber-type remodeling in skeletal muscle. This mechanism identifies cardiolipin regulation as a possible therapeutic target for age-related muscle decline and myopathies.

Caveats

Most causal findings rely on an inducible genetic knockout in mice rather than naturally aged animals. Although human muscle was examined to link cardiolipin to aging, whether targeting this pathway can treat muscle aging in humans remains untested.