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.