Abstract
Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Here we show that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibres, associated with a small increase in the number of oxidative fibres. This shift in fibre composition results in muscles with slower myofiber contraction and relaxation, and also decreases whole-body oxygen consumption, reduces spontaneous activity, increases adiposity and glucose intolerance. Mechanistically, ablation of Tbx15 leads to activation of AMPK signalling and a decrease in Igf2 expression. Thus, Tbx15 is one of a limited number of transcription factors to be identified with a critical role in regulating glycolytic fibre identity and muscle metabolism.
Highlights
Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology
In C2C12 myoblasts, expression of Tbx[15] messenger RNA increased B12-fold during differentiation, and this was confirmed by western blot analysis (Fig. 1b)
Assessment of individual muscles showed that Tbx[15] messenger RNA (mRNA) was over two-fold higher in glycolytic muscles, such as the extensor digitorum longus (EDL), gastrocnemius and tibialis anterior, than in the oxidative muscle, such as soleus; and this was confirmed by western blot analysis (Fig. 1d)
Summary
Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Ablation of Tbx[15] in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibres, associated with a small increase in the number of oxidative fibres. This shift in fibre composition results in muscles with slower myofiber contraction and relaxation, and decreases whole-body oxygen consumption, reduces spontaneous activity, increases adiposity and glucose intolerance. Tbx[15] is one of a limited number of transcription factors to be identified with a critical role in regulating glycolytic fibre identity and muscle metabolism. Tbx[15] can activate gene transcription, or through its interactions with co-repressors of the Groucho family, repress gene transcription[18]
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