Nuclear Lamina Dysfunction in Mesenchymal Progenitors Drives Muscle Pathogenesis

The nuclear lamina (NL) is a critical component of mammalian cells that provide structural support to the nucleus, contributing to genome organization and gene regulation, thus regulating cell identity and functions. The NL is composed of two different types of nuclear lamins, A-type and B-type lamins, encoded by the LMNA and LMNB1/2 genes, respectively. Mutations in LMNA cause a heterogeneous group of disorders, collectively known as laminopathies, that most prominently involve striated muscles, leading to cardiomyopathies and muscular dystrophies. Although pathogenic mechanisms have been mainly attributed to defects intrinsic to myofibers and muscle stem cells (MuSCs), these models d not fully explain disease progression, suggesting that dysfunction of the regenerative niche may play a critical role. FibroAdipogenic Progenitors (FAPs) are mesenchymal stromal cells essential for muscle repair, supporting MuSC activation and differentiation but, under pathological conditions, driving fibro-fatty degeneration. Despite their central role in other muscular dystrophies, their contribution to EDMD remains unexplored. In this work, we propose that LMNA loss of function disrupts FAP identity and function, thereby altering the stromal environment required for effective regeneration. To address this, we generated a FAP-specific Lmna conditional knock-ou (cKO) mouse. Here, we show that Lamin A/C loss in FAPs is sufficient to impair muscle regeneration, reduce muscle mas and strength, and disrupt tissue architecture. Notably, Lamin A/C–deficient FAPs fail to support MuSC differentiation, indicating that stromal dysfunction alone can compromise myogenesis through non–cell-autonomous mechanisms. Taken together, these data indicate that FAPs-specific dysfunctions in the NL are sufficient to reshape the regenerative niche compromising muscle homeostasis, thus revealing new stromal targets for therapy and opening new avenues of research in laminopathies.