Developmental epigenetic circuits and their epigenetic drift in skeletal muscle ageing

Development and ageing are two deeply intertwined processes, but it remains unclear how programmes established during early development influence the long-term stability of post-mitotic tissues. Skeletal muscle provides a model of choice to study the connection between these processes. Myofibres are long-lived, multinucleated syncytia whose identity and homeostasis rely on transcriptional, metabolic and epigenetic states established during embryonic and postnatal development. Throughout life, these states are further reinforced by satellite cell-derived inputs. In this review, we discuss how early specification cues, chromatin architecture and metabolic wiring establish durable regulatory circuits preserving myofibre integrity but also limiting its plasticity across the lifespan. These developmental features, combined with decades of physiological strain, progressively challenge genomic integrity and destabilize the maintenance of epigenetic information. Over time, this instability causes an epigenetic drift, encompassing alterations in DNA methylation, changes in histone landscapes and disruption in higher-order chromatin organization. Such alterations erode transcriptional fidelity and contribute to the appearance of hallmarks of the ageing phenotype. By integrating developmental and epigenetic perspectives, we argue that myofibre ageing reflects not only cumulative damage but also the long-term consequences of how these exceptionally long-lived cells were originally built. This article is part of the theme issue 'Developmental circuits in ageing'.