A growing number of evidences indicates that histone variants gradually replace conventional histones during post-natal life. However, the functional and physiological signification of this progressive replacement remains poorly described. Using HSA-cre driver mice, we have specifically invalidated in muscle fibers the H2A.Z1 and H2A.Z2 genes that encode for the histone variant H2AZ. At one year of age, H2A.Z KO muscles have a similar histology than 30 months old WT muscles and exhibit all the features of muscle aging (muscle atrophy, centronucleated fibers, severe mitochondrial and neuromuscular junction alterations, increased oxidative stress and protein carbonylation, accumulation of DNA damage and reduced lifespan). Moreover, the transcriptome of H2A.Z KO muscles perfectly matches published transcriptomic analysis of aged muscle.
Investigation of the molecular mechanisms involved shows that H2AZ-containing nucleosomes recruit DNA repair proteins at DNA lesions via direct interactions. It is known that DNA repair deficiency causes premature aging and progeroid syndromes, and the current view is that it is responsible for mitochondrial alterations and impairment of nucleus-to-mitochondria signaling. Our mouse model pleads in favour of this theory: by preventing DNA repair, H2AZ depletion induces the accumulation of lesions in muscle fibers, resulting in severe mitochondrial dysfunction. Altogether, H2AZ KO muscles provide an in vivo model in which the rate of DNA damage accumulation is increased, and this is sufficient to induce premature aging.
Human epidemiologic studies and animal models indicate that skeletal muscle is a key determinant of lifespan (Demontis et al., 2013). Most studies on the systemic role of skeletal muscle were performed in an aging or pathological context in which it is not easy to isolate the respective contribution of the various tissues in lifespan expectancy. By specifically inducing premature aging in muscle fibers, our model provides unbiased evidence that provoking accelerated aging in post mitotic muscle fibers is sufficient to reduce lifespan. 

E. Belloti, N. Lacoste, T. Simonet, P.O. Mari, N. Streichenberger, C. Papin, E. Girard, G. Giglia Mari, S. Dimitrov, A. Hamiche, L. Schaeffer