Abstracts from the Annual Conference on Aging Mayan Ranch Texas Hill Country Bandera Texas USA 2013

摘要

Motor neurons form a specialized synapse with skeletal muscle known as the neuromuscular junction (NMJ), and degeneration of the NMJ has been implicated in disease and aging. Histone deacetylases mediate NMJ-regulated gene transcription and are involved in neurogenic muscle atrophy, although their role in age-related muscle atrophy is not known. HDAC4 and HDAC5 knockout mice are protected against surgical denervation, and pharmacological inhibition of histone deacetylases is protective in multiple models of neuromuscular disease. In this study, we examined the effect of butyrate, a histone deacetylase inhibitor, on muscle atrophy during sciatic nerve crush and age-related muscle atrophy. We demonstrate that butyrate increases histone acetylation in vivo and protects against the muscle loss induced by sciatic nerve crush and aging. Control-fed mice lost 22% of their gastrocnemius mass while the butyrate-fed mice lost only 11% one week after sciatic nerve crush surgery. Butyrate protects against the loss of cross-sectional area, increases catalase and MnSOD activity, and reduces oxidative damage during nerve crush. Consistently, butyrate protects against age-related muscle atrophy in mice by modulating antioxidant activity, reducing oxidative damage, and increasing mitochondrial biogenesis. We also report improved metabolism in old mice fed butyrate, including improved glucose tolerance and increased whole-body oxygen consumption. Future studies will determine the mechanism by which butyrate protects against age-related muscle atrophy.