Reduced LANCL1-AS1 in old human skeletal muscle diminishes mitochondrial activity, shortens mt-mRNA poly(A) tails, and suppresses myogenesis

Yang, J.-H., Izydore, E. K., Mazan-Mamczarz, K., Tsitsipatis, D., Mattison, J. A., Romero, B., Shi, C., Yang, X., Munk, R., Martindale, J. L., Anerillas, C., Salamini-Montemurri, M., Rossi, M., Piao, Y., Fan, J., Chen, Y.-C., Cedeno-Veloz, B. A., Ferrero, R., Montes, M., Martinez-Velilla, N., Chu, T.-H., Abdelmohsen, K., Cui, C.-Y., Batish, M., De, S., Sen, P., Ferrucci, L., de Cabo, R., Gorospe, M.

NIA IRP, NIHNIA IRP, NIH · biorxiv

Paper

Abstract

Regeneration of skeletal muscle preserves muscle mass and function, which decline with age. Here, we sought to identify long noncoding (lnc)RNAs involved in skeletal muscle myogenesis and potentially relevant to muscle aging. Cross-sectional analysis of skeletal muscle transcriptomes from healthy 22-through 89-year-old individuals revealed lncRNA LANCL1-AS1 among the top declining transcripts. Conversely, LANCL1-AS1 increased robustly during skeletal myogenesis and promoted myogenic differentiation in culture. Affinity pulldown by ChIRP followed by mass spectrometry revealed that LANCL1-AS1 associated with the mitochondrial protein LRPPRC, enhancing the formation of the chaperone complex LRPPRC-SLIRP, which maintains longer poly(A) tails of mitochondrial (mt-)mRNAs and stabilizes mt-mRNAs. Importantly, while myoblasts from old rhesus monkey muscle expressed lower levels of LANCL1-AS1 and mt-mRNAs, and displayed lower mitochondrial activity than young monkey myoblasts, overexpressing LANCL1-AS1 in old myoblasts restored mitochondrial activity and myogenesis. We propose that the age-associated reduction in LANCL1-AS1 contributes to impaired mitochondrial function and reduced myogenic capacity in aging skeletal muscle.

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Research summary

The study identifies the lncRNA LANCL1-AS1 as a regulator of mitochondrial mRNA stability and myogenesis that declines with age, demonstrating that its restoration can rescue mitochondrial function and differentiation in aged muscle cells. This work is relevant because it targets fundamental hallmarks of aging (mitochondrial dysfunction and stem cell exhaustion) rather than just treating symptoms, offering a mechanistic insight into muscle aging, though the direct translation to lifespan extension remains unproven.

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