Epigenetic control of skeletal muscle regeneration: Integrating genetic determinants and environmental changes

During embryonic development, pluripotent cells are genetically committed to specific lineages by the expression of cell-type-specific transcriptional activators that direct the formation of specialized tissues and organs in response to developmental cues. Chromatin-modifying proteins are emerging as essential components of the epigenetic machinery, which establishes the nuclear landscape that ultimately determines the final identity and functional specialization of adult cells. Recent evidence has revealed that discrete populations of adult cells can retain the ability to adopt alternative cell fates in response to environmental cues. These cells include conventional adult stem cells and a still poorly defined collection of cell types endowed with facultative phenotype and functional plasticity. Under physiological conditions or adaptive states, these cells cooperate to support tissue and organ homeostasis, and to promote growth or compensatory regeneration. However, during chronic diseases and aging these cells can adopt a pathological phenotype and mediate maladaptive responses, such as the formation of fibrotic scars and fat deposition that progressively replaces structural and functional units of tissues and organs. The molecular determinants of these phenotypic transitions are only emerging from recent studies that reveal how dynamic chromatin states can generate flexible epigenetic landscapes, which confer on cells the ability to retain partial pluripotency and adapt to environmental changes. This review summarizes our current knowledge on the role of the epigenetic machinery as a 'filter' between genetic commitment and environmental signals in cell types that can alternatively promote skeletal muscle regeneration or fibro-adipogenic degeneration.