Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A.
Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A.
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DOI：
10.1073/pnas.2019263117
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发表时间：
2020-12-08
影响因子：
11.1
通讯作者：
Rando TA
中科院分区：
文献类型：
--
作者：
Lee SJ;Lehar A;Liu Y;Ly CH;Pham QM;Michaud M;Rydzik R;Youngstrom DW;Shen MM;Kaartinen V;Germain-Lee EL;Rando TA
肌生长抑制素和激活素A是分泌的信号分子，其作用是限制骨骼肌生长。在这里，我们表明，肌肉生长抑制素和激活素A利用四个受体成分直接向肌纤维发出信号。这些发现对靶向这种信号通路用于临床应用以治疗肌肉损失患者的策略具有影响。肌生长抑制素（Myostatin，MSTs）是一种转化生长因子-β（TGF-β）家族成员，在正常情况下起限制肌肉生长的作用。Mc的功能与另一个TGF-β家族成员激活素A的功能部分冗余。Mc和激活素A能够通过II型和I型受体的复合物进行信号传导。在这里，我们研究了两种II型受体（ACVR 2和ACVR 2B）和两种I型受体（ALK 4和ALK 5）在这些配体调节肌肉质量中的作用，通过遗传靶向这些受体单独或组合特异性地在小鼠肌纤维中。我们发现，在肌纤维中的靶向信号传导足以引起肌肉质量的显着增加，表明肌纤维是这些配体在肌肉生长调节中的信号传导的直接靶点。此外，我们表明，有两个II型受体之间的功能冗余，以及两个I型受体之间，所有四个II型/I型受体的组合在体内使用。在肌纤维中特异性靶向信号传导还导致了喂食常规食物或高脂肪饮食的小鼠体内总体脂肪含量的减少和葡萄糖代谢的改善，这表明这些代谢效应是增强肌肉的结果。然而，我们没有观察到对小鼠的骨密度或肌肉再生的影响，其中信号传导是以肌纤维为目标的。后一个发现意味着除了肌纤维外，肌钙蛋白可能还向其他细胞（如卫星细胞）发出信号，以调节肌肉稳态。
Myostatin and activin A are secreted signaling molecules that act to limit skeletal muscle growth. Here, we show that myostatin and activin A utilize four receptor components to signal directly to muscle fibers. These findings have implications for strategies to target this signaling pathway for clinical applications to treat patients with muscle loss. Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.
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影响因子：
3.9
作者：
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DOI：
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影响因子：
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