Odria Renato, Cardús Aina, Gomis-Coloma Clara, Balanyà-Segura Marta, Mercado-Amarilla Alexandra, Maestre-Mora Pau, Poveda-Sabuco Andrea, Domingo Joan Carles, Nogales-Gadea Gisela, Gomez-Sanchez Jose A, Hurtado Erica, Suelves Mònica
Grup de Recerca en Malaties Neuromusculars de Badalona (GRENBA), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), 08916, Badalona, Spain.
Programa de Doctorat en Biomedicina, Universitat de Barcelona, 08007, Barcelona, Spain.
Geroscience. 2025 Apr 12. doi: 10.1007/s11357-025-01611-y.
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.
肌肉减少症被定义为与衰老相关的骨骼肌质量和功能的逐渐丧失，对老年人的生活质量产生了毁灭性影响。肌肉衰老的特征是肌肉萎缩和肌肉修复能力下降，包括肌肉干细胞池减少，这会阻碍损伤后的恢复。组蛋白去乙酰化酶11（HDAC11）是HDAC家族的最新成员，在骨骼肌中高度表达。我们的研究小组最近发现，HDAC11基因缺陷可增强年轻小鼠的骨骼肌再生、线粒体功能，并全面改善肌肉性能。在此，我们首次探讨了HDAC11缺陷在老年小鼠体内、稳态以及肌肉再生过程中的功能后果。缺乏HDAC11的老年小鼠表现出肌肉萎缩减轻和神经肌肉接头突触后碎片化，但外周神经有髓轴突的数量或直径没有显著差异。还观察到肌肉干细胞库的维持以及损伤后骨骼肌的高级再生。HDAC11的缺失增强了线粒体脂肪酸氧化，并减轻了骨骼肌脂肪酸组成中与年龄相关的变化，大幅降低了ω-6/ω-3脂肪酸比率，并显著提高了ω-3指数，这为肌肉力量增强、抗疲劳能力提高和死亡率降低提供了解释。综上所述，我们的结果表明HDAC11是治疗肌肉减少症的新靶点。重要的是，最近已经开发出选择性HDAC11抑制剂，这可能为延缓衰老过程提供一种新的治疗方法。
