Aging associates with progressive loss of skeletal muscle function leading up to sarcopenia, a process characterized by impaired mobility and weakening of muscle strength. Molecular mechanisms underpinning sarcopenia are still poorly characterized. Since aging associates with profound epigenetic changes, epigenetic landscape alteration analysis in the skeletal muscle promises to highlight molecular mechanisms of age-associated sarcopenia. The study was conducted exploiting the short-lived turquoise killifish Nothobranchius furzeri (Nfu), a relatively new model for aging studies. The epigenetic analysis suggested for a less accessible and more condensed chromatin in old Nfu skeletal muscle. Specifically, an accumulation of heterochromatin regions was observed as consequence of increased levels of H3K27me3, HP1alpha, polycomb complex subunits and senescence associated heterochromatic foci (SAHFs). Consistently, euchromatin histone marks, including H3K9ac, decreased. The integrative bioinformatics analysis of RNASeq and ChIPSeq, related to skeletal muscle of Nfu at different ages, revealed a down-modulation of genes involved in cell cycle, differentiation and DNA repair and an up-regulation of inflammation and senescence genes. Undoubtedly, more studies are needed to disclose the detailed mechanisms, but this approach revealed an unprecedented specific features of Nfu skeletal muscle aging, potentially associated with sarcopenia onset and consequent impairment of swimming and mobility typical of old Nfu.