Progressive muscle atrophy is characteristic of several chronic debilitating conditions, including ageing (sarcopenia), muscular dystrophies, diabetes, bedrest and spaceflight. Whilst the precise mechanisms of slow atrophy are poorly defined and… Click to show full abstract
Progressive muscle atrophy is characteristic of several chronic debilitating conditions, including ageing (sarcopenia), muscular dystrophies, diabetes, bedrest and spaceflight. Whilst the precise mechanisms of slow atrophy are poorly defined and multifactorial, impaired mitochondrial ‘function’ (e.g. oxidative capacity and fusion-fission dynamics) is a common feature and represents an attractive target for therapy. Nonetheless, effective countermeasures remain elusive. Hydrogen sulfide (H2S) is an endogenous ‘gasotransmitter’ with important roles in several biochemical processes, including the maintenance of mitochondrial integrity, and in models of ageing ‘H2S bioavailability’ is significantly reduced. Using Caenorhabditis elegans as an established model for muscle ageing, we have examined the role of a novel class of H2S donors for promoting healthspan and lifespan. Unlike general non-targeted H2S donor compounds with established efficacy in extending lifespan (e.g. GYY4137), we have examined compounds that drive targeted H2S directly to the mitochondria by coupling H2S-generating moieties to a triphenylphosphonium motif (AP39) or mitochondria-targeting peptide sequences (RTP10). Our study shows that these compounds effectively preserve mitochondrial structure versus non-targeted H2S donors (mitochondria::GFP fragmentation: AP39 = ≥10 d, GYY4137 = 6 d post-adulthood). Mitochondrial H2S also improved animal movement rate (movement across the lifespan (mean ± SEM): AP39 = 73.2 ± 9.6, GYY4137 = 57.6 ± 27.6 strokes.min-1, P
               
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