Department of Pathology and Pathophysiology and Department of Cardiology, School of Medicine, Second Affiliated Hospital, Zhejiang University, Hangzhou, China.
Department of Endocrinology and Metabolism, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China.
J Exp Med. 2023 Sep 4;220(9). doi: 10.1084/jem.20221123. Epub 2023 Jun 7.
Obesity and type 2 diabetes (T2D) are the leading causes of the progressive decline in muscle regeneration and fitness in adults. The muscle microenvironment is known to play a key role in controlling muscle stem cell regenerative capacity, yet the underlying mechanism remains elusive. Here, we found that Baf60c expression in skeletal muscle is significantly downregulated in obese and T2D mice and humans. Myofiber-specific ablation of Baf60c in mice impairs muscle regeneration and contraction, accompanied by a robust upregulation of Dkk3, a muscle-enriched secreted protein. Dkk3 inhibits muscle stem cell differentiation and attenuates muscle regeneration in vivo. Conversely, Dkk3 blockade by myofiber-specific Baf60c transgene promotes muscle regeneration and contraction. Baf60c interacts with Six4 to synergistically suppress myocyte Dkk3 expression. While muscle expression and circulation levels of Dkk3 are markedly elevated in obese mice and humans, Dkk3 knockdown improves muscle regeneration in obese mice. This work defines Baf60c in myofiber as a critical regulator of muscle regeneration through Dkk3-mediated paracrine signaling.
肥胖和 2 型糖尿病（T2D）是导致成年人肌肉再生和功能逐渐下降的主要原因。肌肉微环境被认为在控制肌肉干细胞再生能力方面起着关键作用，但潜在的机制仍难以捉摸。在这里，我们发现肥胖和 T2D 小鼠和人类的骨骼肌中 Baf60c 的表达显著下调。在小鼠中，肌纤维特异性敲除 Baf60c 会损害肌肉再生和收缩，同时肌肉丰富的分泌蛋白 Dkk3 显著上调。Dkk3 抑制肌肉干细胞分化并减弱体内肌肉再生。相反，肌纤维特异性 Baf60c 转基因通过 Dkk3 阻断促进肌肉再生和收缩。Baf60c 与 Six4 相互作用，协同抑制肌细胞 Dkk3 的表达。虽然肥胖小鼠和人类的肌肉表达和循环 Dkk3 水平显著升高，但 Dkk3 敲低可改善肥胖小鼠的肌肉再生。这项工作定义了肌纤维中的 Baf60c 通过 Dkk3 介导的旁分泌信号作为肌肉再生的关键调节剂。
