Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Department of Pathology, The Ohio State University, Columbus, OH, USA.
Nat Commun. 2022 Jan 10;13(1):168. doi: 10.1038/s41467-021-27848-7.
Skeletal muscle serves fundamental roles in organismal health. Gene expression fluctuations are critical for muscle homeostasis and the response to environmental insults. Yet, little is known about post-transcriptional mechanisms regulating such fluctuations while impacting muscle proteome. Here we report genome-wide analysis of mRNA methyladenosine (mA) dynamics of skeletal muscle hypertrophic growth following overload-induced stress. We show that increases in METTL3 (the mA enzyme), and concomitantly mA, control skeletal muscle size during hypertrophy; exogenous delivery of METTL3 induces skeletal muscle growth, even without external triggers. We also show that METTL3 represses activin type 2 A receptors (ACVR2A) synthesis, blunting activation of anti-hypertrophic signaling. Notably, myofiber-specific conditional genetic deletion of METTL3 caused spontaneous muscle wasting over time and abrogated overload-induced hypertrophy; a phenotype reverted by co-administration of a myostatin inhibitor. These studies identify a previously unrecognized post-transcriptional mechanism promoting the hypertrophic response of skeletal muscle via control of myostatin signaling.
骨骼肌在机体健康中起着重要的作用。基因表达的波动对于肌肉的内稳态和对环境损伤的反应至关重要。然而，对于调节这些波动并影响肌肉蛋白质组的转录后机制知之甚少。在这里，我们报道了在超负荷诱导的应激后骨骼肌肥大生长过程中，mRNA 甲基腺苷（mA）动力学的全基因组分析。我们发现，METTL3（mA 酶）的增加，以及随之而来的 mA，在肥大过程中控制着骨骼肌的大小；外源性 METTL3 的递送即使没有外部触发也能诱导骨骼肌生长。我们还发现，METTL3 抑制激活素受体 2A（ACVR2A）的合成，从而削弱了抗肥大信号的激活。值得注意的是，肌纤维特异性条件性基因敲除 METTL3 会导致肌肉随着时间的推移自发消耗，并消除超负荷诱导的肥大；而肌抑素抑制剂的共同给药则可逆转这一表型。这些研究确定了一种以前未被识别的转录后机制，通过控制肌抑素信号促进骨骼肌的肥大反应。
