Exercise mitigates the effects of hyperhomocysteinemia on adverse muscle remodeling

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.