Prdm16 preserves nuclear lamina integrity and mitotic fidelity in FAPs to prevent muscle aging

Aging leads to a progressive decline in tissue homeostasis and regenerative capacity, driven in part by diminished stem cell function and disrupted interactions within their niche. These changes are closely associated with widespread epigenetic alterations, including the loss of constitutive heterochromatin and disorganization of the nuclear lamina (NL)—key hallmarks of cellular aging. We previously identified Prdm16 as a pivotal regulator of heterochromatin anchoring at the NL, particularly enriched in fibro-adipogenic progenitors (FAPs). Here, we demonstrate that Prdm16 is essential for preserving NL integrity in FAPs. Loss of Prdm16 leads to structural disorganization of the NL, culminating in its rupture, genomic instability, and the onset of senescence-associated features. Time-lapse imaging further reveals that Prdm16 safeguards mitotic fidelity, with its absence resulting in cytokinesis failure and aneuploidy. In vivo, our data indicate that FAPs-specific disruption of NL integrity impairs skeletal muscle homeostasis and regeneration, underscoring Prdm16’s critical role in protecting against premature muscle deterioration during aging.