Department of Biology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy.
J Cell Biochem. 2012 Jun;113(6):2057-63. doi: 10.1002/jcb.24077.
Skeletal muscle has the ability to regenerate new muscle fibers after injury. The process of new muscle formation requires that quiescent mononuclear muscle precursor cells (myoblasts) become activated, proliferate, differentiate, and fuse into multinucleated myotubes which, in turn, undergo further differentiation and mature to form functional muscle fibers. Previous data demonstrated the crucial role played by 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMGR), the rate-limiting enzyme of cholesterol biosynthetic pathway, in fetal rat myoblast (L6) differentiation. This finding, along with epidemiological studies assessing the myotoxic effect of statins, HMGR inhibitors, allowed us to speculate that HMGR could be strongly involved in skeletal muscle repair. Thus, our research was aimed at evaluating such involvement: in vitro and in vivo experiments were performed on both mouse adult satellite cell derived myoblasts (SCDM) and mouse muscles injured with cardiotoxin. Results demonstrate that HMGR inhibition by the statin Simvastatin reduces SCDM fusion index, fast MHC protein levels by 60% and slow MHC by 40%. Most importantly, HMGR inhibition delays skeletal muscle regeneration in vivo. Thus, besides complaining of myopathies, patients given Simvastatin could also undergo an impairment in muscle repair.
骨骼肌在受伤后具有再生新肌纤维的能力。新肌肉形成的过程需要静息的单核肌前体细胞（成肌细胞）被激活、增殖、分化，并融合成多核肌管，然后进一步分化和成熟，形成具有功能的肌纤维。先前的数据表明，3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGR）在胎儿大鼠成肌细胞（L6）分化中起着至关重要的作用，HMGR 是胆固醇生物合成途径的限速酶。这一发现，以及评估他汀类药物、HMGR 抑制剂对肌肉毒性作用的流行病学研究，使我们推测 HMGR 可能在骨骼肌修复中起重要作用。因此，我们的研究旨在评估这种作用：在体外和体内实验中，我们分别使用成年小鼠卫星细胞衍生的成肌细胞（SCDM）和用心脏毒素损伤的小鼠肌肉进行了实验。结果表明，他汀类药物辛伐他汀抑制 HMGR 会降低 SCDM 融合指数，使快肌 MHC 蛋白水平降低 60%，慢肌 MHC 蛋白水平降低 40%。最重要的是，HMGR 抑制会延迟体内骨骼肌再生。因此，除了抱怨肌病外，服用辛伐他汀的患者还可能出现肌肉修复受损。
