Hyperhomocysteinemia (HHcy) is associated with elderly
frailty, skeletal muscle injury and malfunction, reduced vascular integrity and function, and mortality. Although HHcy has been implicated in the impairment of angiogenesis after hindlimb
ischemia in murine models, the underlying mechanisms are still unclear. We hypothesized that HHcy compromises skeletal muscle perfusion, collateral formation, and arteriogenesis by diminishing postischemic vasculogenic responses in muscle fibers. To test this hypothesis, we created femoral artery
ligation in wild-type and heterozygous
cystathionine β-synthase (CBS(+/-)) mice (a model for HHcy) and assessed tissue perfusion, collateral vessel formation, and skeletal muscle function using
laser-Doppler perfusion imaging,
barium angiography, and
fatigue tests. In addition, we assessed postischemic levels of
VEGF and levels of its muscle-specific regulators:
hypoxia-inducible factor (HIF)-1α and
peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α. The observations indicated dysregulation of
VEGF, HIF-1α, and PGC-1α levels in ischemic skeletal muscles of CBS(+/-) mice. Concomitant with the reduced ischemic angiogenic responses, we also observed diminished
leptin expression and attenuated Akt signaling in ischemic muscle fibers of CBS(+/-) mice. Moreover, there was enhanced atrogene,
ubiquitin ligases that conjugate
proteins for degradation during
muscle atrophy, transcription, and reduced muscle function after
ischemia in CBS(+/-) mice. These results suggest that HHcy adversely affects muscle-specific ischemic responses and contributes to muscle
frailty.