Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, AZ 85724, USA.
Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
Sci Adv. 2024 Mar 15;10(11):eadk1890. doi: 10.1126/sciadv.adk1890. Epub 2024 Mar 13.
Muscle contraction is a regulated process driven by the sliding of actin-thin filaments over myosin-thick filaments. Lmod2 is an actin filament length regulator and essential for life since human mutations and complete loss of Lmod2 in mice lead to dilated cardiomyopathy and death. To study the little-known role of Lmod2 in skeletal muscle, we created a mouse model with Lmod2 expressed exclusively in the heart but absent in skeletal muscle. Loss of Lmod2 in skeletal muscle results in decreased force production in fast- and slow-twitch muscles. Soleus muscle from rescued knockout mice have shorter thin filaments, increased Lmod3 levels, and present with a myosin fiber type switch from fast myosin heavy chain (MHC) IIA to the slower MHC I isoform. Since Lmod2 regulates thin-filament length in slow-twitch but not fast-twitch skeletal muscle and force deficits were observed in both muscle types, this work demonstrates that Lmod2 regulates skeletal muscle contraction, independent of its role in thin-filament length regulation.
肌肉收缩是一个受调节的过程，由肌动蛋白细丝在肌球蛋白粗丝上滑动驱动。Lmod2 是一种肌动蛋白丝长度调节剂，对生命至关重要，因为人类突变和小鼠中 Lmod2 的完全缺失会导致扩张型心肌病和死亡。为了研究 Lmod2 在骨骼肌中的鲜为人知的作用，我们创建了一种仅在心脏中表达 Lmod2 而在骨骼肌中缺失的小鼠模型。骨骼肌中 Lmod2 的缺失导致快肌和慢肌的力量产生减少。从挽救的 敲除小鼠的比目鱼肌中，我们观察到更短的细肌丝、Lmod3 水平升高，以及肌球蛋白纤维类型从快肌肌球蛋白重链（MHC）IIA 向更慢的 MHC I 同工型的转变。由于 Lmod2 调节慢肌中的细肌丝长度，但不调节快肌中的细肌丝长度，并且在两种肌肉类型中都观察到力量缺陷，因此这项工作表明 Lmod2 调节骨骼肌收缩，独立于其在细肌丝长度调节中的作用。
