Children born with severe homocystinuria due to homozygous cystathionine beta synthase deficiency (CBS-/-) exhibit poor body weights, skeletal muscle myopathy and die in teenage. Although mice with homozygous CBS mutation die shortly after birth, the heterozygous CBS-/+ survives. Our preliminary data suggests that enzymes, CBS and cystathionine gamma-lyase (CSE) that irreversibly remove homocysteine (Hcy) by converting to hydrogen sulfide (H2S), are decreased in skeletal muscle. Although lowering of Hcy levels and generation of H2S is beneficial, the mechanism by which HHcy causes of skeletal muscle wasting and frailty is unknown. The long-term goal of this project is to understand the mechanism of muscle wasting in HHcy and evaluate the potential beneficial effects of H2S signaling in reversing skeletal muscle wasting and myopathy. The central hypothesis of this proposal is that HHcy causes skeletal muscle deterioration by compromising vasculogenesis, by enhancing muscle atrophy and by limiting skeletal muscle regeneration and H2S reverses these changes. We will test this hypothesis by following three specific aims:
Specific Aim #1 : To determine whether the HHcy inhibits muscle specific AKT, HIF-1, and AMPK signaling and impairs vasculogenesis and H2S reverses impaired vasculogenesis.
Specific Aim #2 : To determine whether the HHcy attenuates PGC-1 signaling and instigates atrogene expression and causes muscular atrophy and H2S mitigates muscle atrophy.
Specific Aim #3 : To determine whether the HHcy enhances TGF-?1 signaling and myostatin levels, thereby suppresses muscle regeneration and H2S ameliorates these changes.
This proposal is aimed to understand the mechanistic role of metabolic alterations (i.e. HHcy) in muscular damage and to evaluate the therapeutic potential of this novel gaseous signaling molecule, H2S. This study will also reveal that the H2S generation itself is enough to counter the HHcy mediated detrimental effects necessary to benefit therapeutic modalities.