HDAC11 deficiency regulates age-related muscle decline and sarcopenia

Identifier:  imarina:9452207

Handle: https://hdl.handle.net/20.500.11797/imarina9452207

Authors:  Odria, R; Cardús, A; Gomis-Coloma, C; Balanyà-Segura, M; Mercado-Amarilla, A; Maestre-Mora, P; Poveda-Sabuco, A; Domingo, JC; Nogales-Gadea, G; Gomez-Sanchez, JA; Hurtado, E; Suelves, M

Abstract:
Sarcopenia, defined as the progressive loss of skeletal muscle mass and function associated with ageing, has devastating effects in terms of reducing the quality of life of older people. Muscle ageing is characterised by muscle atrophy and decreased capacity for muscle repair, including a reduction in the muscle stem cell pool that impedes recovery after injury. Histone deacetylase 11 (HDAC11) is the newest member of the HDAC family and it is highly expressed in skeletal muscle. Our group recently showed that genetic deficiency in HDAC11 increases skeletal muscle regeneration, mitochondrial function and globally improves muscle performance in young mice. Here, we explore for the first time the functional consequences of HDAC11 deficiency in old mice, in homeostasis and during muscle regeneration. Aged mice lacking HDAC11 show attenuated muscle atrophy and postsynaptic fragmentation of the neuromuscular junction, but no significant differences in the number or diameter of myelinated axons of peripheral nerves. Maintenance of the muscle stem cell reservoir and advanced skeletal muscle regeneration after injury are also observed. HDAC11 depletion enhances mitochondrial fatty acid oxidation and attenuates age-associated alterations in skeletal muscle fatty acid composition, reducing drastically the omega-6/omega-3 fatty acid ratio and improving significantly the omega-3 index, providing an explanation for improved muscle strength and fatigue resistance and decreased mortality. Taken together, our results point to HDAC11 as a new target for the treatment of sarcopenia. Importantly, selective HDAC11 inhibitors have recently been developed that could offer a new therapeutic approach to slow the ageing process.