Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Cell Rep. 2021 Jan 5;34(1):108594. doi: 10.1016/j.celrep.2020.108594.
Skeletal muscle regeneration after injury is essential for maintaining muscle function throughout aging. ARHGEF3, a RhoA/B-specific GEF, negatively regulates myoblast differentiation through Akt signaling independently of its GEF activity in vitro. Here, we report ARHGEF3's role in skeletal muscle regeneration revealed by ARHGEF3-KO mice. These mice exhibit indiscernible phenotype under basal conditions. Upon acute injury, however, ARHGEF3 deficiency enhances the mass/fiber size and function of regenerating muscles in both young and regeneration-defective middle-aged mice. Surprisingly, these effects occur independently of Akt but via the GEF activity of ARHGEF3. Consistently, overexpression of ARHGEF3 inhibits muscle regeneration in a Rho-associated kinase-dependent manner. We further show that ARHGEF3 KO promotes muscle regeneration through activation of autophagy, a process that is also critical for maintaining muscle strength. Accordingly, ARHGEF3 depletion in old mice prevents muscle weakness by restoring autophagy. Taken together, our findings identify a link between ARHGEF3 and autophagy-related muscle pathophysiology.
损伤后的骨骼肌再生对于维持整个衰老过程中的肌肉功能至关重要。ARHGEF3 是一种 RhoA/B 特异性 GEF，通过 Akt 信号通路独立于其 GEF 活性在体外负调控成肌细胞分化。在这里，我们通过 ARHGEF3-KO 小鼠报告了 ARHGEF3 在骨骼肌再生中的作用。这些小鼠在基础条件下表现出不可察觉的表型。然而，在急性损伤时，ARHGEF3 缺乏增强了年轻和再生缺陷中年小鼠再生肌肉的质量/纤维大小和功能。令人惊讶的是，这些效应独立于 Akt 发生，而是通过 ARHGEF3 的 GEF 活性。一致地，ARHGEF3 的过表达以依赖 Rho 相关激酶的方式抑制肌肉再生。我们进一步表明，ARHGEF3 KO 通过激活自噬促进肌肉再生，这一过程对于维持肌肉力量也很关键。因此，在老年小鼠中耗尽 ARHGEF3 通过恢复自噬来预防肌肉无力。总之，我们的发现确定了 ARHGEF3 与自噬相关肌肉病理生理学之间的联系。
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