The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Abstract

SummarySarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age‐related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26‐month‐old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross‐sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26‐month‐old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole‐body oxygen consumption without affecting activity. The increase in mass in butyrate‐treated mice was not due to reduced ubiquitin‐mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age‐related muscle atrophy and may be effective targets for intervention in sarcopenia and age‐related metabolic disease.

Targeting chromatin aging - The epigenetic impact of longevity-associated interventions

“…It is becoming evident that histone acetylation plays a more nuanced role in gene regulation, with site specific changes in histone acetylation playing just as important a role as more global alterations (Peleg et al, 2016). It is notable that lifespan increases associated with treatment with histone deacetylase inhibitors (HDACi's) such as trichostatin A (TSA) and butyrate often show more targeted gene-specific effects (Tao et al, 2004;Walsh et al, 2015). There may be a role for both approaches in maximising health and longevity, whereby global reduction in histone acetylation can be paired with gene specific retention of histone acetylation to maintain optimal gene expression programs through the life course, by carefully tailored application of nutritional interventions in conjunction with HDAC inhibitors.…”

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

“…Following denervation, HDAC4 indirectly regulates myogenin expression, thereby connecting neuronal activity to skeletal muscle transcriptional reprogramming of the neuromuscular junctions and compensatory reinnervation [35]. Considering its crucial role, HDAC4 has been proposed as a potential therapeutic target for diseases characterized by neurogenic muscle atrophy, such as ALS or SMA, or for sarcopenia [36][37][38][39]. Any pharmacological treatment with HDAC4 inhibitors for these conditions should be continued for months or years.…”

Possible Prophylaxes of Aloe Vera Gel Ingestion to Butyrate Metabolism

“…Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hind-limb muscles. The data show a beneficial effect of butyrate on muscle mass during aging and suggest HDACs contribute to age-related muscle atrophy and may be effective targets for intervention in sarcopenia and agerelated metabolic disease [12] . Henagan TM.…”

“…Measurement of expired 13 CO2 after rectally administering [1][2][3][4][5][6][7][8][9][10][11][12][13] C]-butyrate in active and quiescent UC appears to be a promising and reliable method for evaluating disease activity and metabolic changes associated with amelioration of inflammation [10] . Gao Z. and his group examined the role of butyrate in the regulation of insulin sensitivity in dietary-obese C57BL/6J mice.…”