SIX1-dependent myofiber typology and metabolism controls muscle hypertrophy
Di Gallo, M.; Delivry, L.; Pereira, D.; Jauliac, E.; Macaux, G.; Guilbert, T.; Denis, R.; Backer, S.; Saintpierre, M.; Adoux, L.; Bernasconi, R.; Laasmaa, M.; Birkedal, R.; Vendelin, M.; Dos Santos, M.; Wojtaszewski, J. F. P.; Foretz, M.; Benoit, V.; Maire, P.; Sotiropoulos, A.; Launay, T.; Britto, F.
Show abstract
The different types of muscle fibres respond in a specific way to hypertrophy or atrophy. The mechanisms underlying these heterogeneous adaptations remain poorly understood. Using single-nucleus RNA sequencing, we propose that fast glycolytic fibres show genetic limitations to hypertrophy induced by mechanical overload. We show that a prior fibre transition, achieved by reducing SIX1 protein expression (hypomorphism), enhances and accelerates overload-induced hypertrophy, bypassing the genetic limitations of fast glycolytic fibres. In contrast and unexpectedly, Six1 knockout in myofibers abolished overload-induced hypertrophy and instead caused atrophy of IIb/IIx fibers, despite the induction of a strong slow oxidative phenotype. In particular, Six1 deletion leads to metabolic defects caused by inhibition of glycolysis, AMPK and mitochondrial biogenesis. Our findings highlight the critical role of SIX1/AMPK/glycolysis-dependent aerobic metabolism in muscle growth and suggest that fibre type transitions, coupled with preserved metabolic function, may optimise hypertrophic responses.
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