Winchester Lee J, Veeranki Sudhakar, Pushpakumar Sathnur, Tyagi Suresh C
School of Kinesiology, Recreation, and Sport, Western Kentucky University, Bowling Green, Kentucky.
Department of Physiology, University of Louisville, Louisville, Kentucky.
Physiol Rep. 2018 Mar;6(6):e13637. doi: 10.14814/phy2.13637.
Hyperhomocysteinemia (HHcy) is known for causing inflammation and vascular remodeling, particularly through production of reactive oxygen species (ROS) and matrix metalloproteinase-9 (MMP-9) activation. Although its effect on the skeletal muscle is unclear, HHcy can cause skeletal muscle weakness and functional impairment by induction of inflammatory mediators and macrophage mediated injury. Exercise has been shown to reduce homocysteine levels and therefore, could serve as a promising intervention for HHcy. The purpose of this study was to investigate whether HHcy causes skeletal muscle fibrosis through induction of inflammation and determine whether exercise can mitigate these effects. C57BL/6J (WT) and CBS+/- (HHcy) mice were administered a 6 weeks treadmill exercise protocol. Hindlimb perfusion was measured via laser Doppler. Measurement of skeletal muscle protein expression was done by western blot. Levels of skeletal muscle MMP-9 mRNA were determined by qPCR. Collagen deposition in the skeletal muscle was measured using Masson's trichrome staining. In CBS+/- mice, HHcy manifested with decreased body weight and femoral artery lumen diameter, as well as a trend of lower hindlimb perfusion. These mice displayed increased wall to lumen ratio, mean arterial blood pressure, collagen deposition, and elevated myostatin protein expression. Exercise mitigated the effects above in CBS+/- mice. Skeletal muscle from CBS+/- mice had elevated markers of remodeling and hypoxia: iNOS, EMMPRIN, and MMP-9. We conclude that HHcy causes skeletal muscle fibrosis possibly through induction of EMMPRIN/MMP-9 and exercise is capable of mitigating the pathologies associated with HHcy.
高同型半胱氨酸血症（HHcy）以引发炎症和血管重塑而闻名，特别是通过产生活性氧（ROS）和基质金属蛋白酶-9（MMP-9）的激活。尽管其对骨骼肌的影响尚不清楚，但HHcy可通过诱导炎症介质和巨噬细胞介导的损伤导致骨骼肌无力和功能障碍。运动已被证明可降低同型半胱氨酸水平，因此，有望成为治疗HHcy的一种干预措施。本研究的目的是调查HHcy是否通过诱导炎症导致骨骼肌纤维化，并确定运动是否可以减轻这些影响。对C57BL/6J（野生型）和CBS+/-（HHcy）小鼠实施为期6周的跑步机运动方案。通过激光多普勒测量后肢灌注。通过蛋白质印迹法测量骨骼肌蛋白表达。通过qPCR测定骨骼肌MMP-9 mRNA水平。使用Masson三色染色法测量骨骼肌中的胶原蛋白沉积。在CBS+/-小鼠中，HHcy表现为体重和股动脉管腔直径降低，以及后肢灌注降低的趋势。这些小鼠的壁腔比、平均动脉血压、胶原蛋白沉积增加，肌肉生长抑制素蛋白表达升高。运动减轻了CBS+/-小鼠的上述影响。CBS+/-小鼠的骨骼肌中重塑和缺氧标志物升高：诱导型一氧化氮合酶（iNOS）、促上皮细胞金属蛋白酶诱导因子（EMMPRIN）和MMP-9。我们得出结论，HHcy可能通过诱导EMMPRIN/MMP-9导致骨骼肌纤维化，并且运动能够减轻与HHcy相关的病理状况。
