FAP adipogenesis drives early spinal muscle loss in dysferlinopathy and reveals a therapeutic target

Abstract

Dysferlinopathy (Limb Girdle Muscular Dystrophy R2/LGMD2B) causes progressive weakness of limb-girdle muscles. Although gait abnormalities are common, the contribution of spinal muscles to disease symptoms remains poorly understood. Using cross-sectional MRI in patients and longitudinal analyses in a dysferlinopathic mouse model, we identify early-onset, progressive adipogenic degeneration of spinal muscles as a previously unrecognized hallmark of dysferlinopathy. Multiple spinal muscles, including the iliocostalis, longissimus, and spinalis, are affected, with degeneration preceding pathology in limb muscles. In mice, early spinal muscle loss is associated with altered posture and gait, implicating axial muscle degeneration as a functional driver of disease. Mechanistically, spinal muscle degeneration is accompanied by an intrinsic increase in adipogenic differentiation of spinal fibroadipogenic progenitors (FAPs). Transcriptomic profiling implicated HDAC and Wnt/ß-catenin signaling as the main regulators of FAP adipogenic shift. Pharmacological inhibition of either pathway suppressed adipogenic differentiation of dysferlinopathic FAPs in vitro, with in vivo inhibition of GSK3 reducing adipogenic degeneration in spinal and injured limb muscles. These findings establish early spinal muscle degeneration as a key pathological feature of dysferlinopathy and identify GSK3 signaling as a promising therapeutic target. Early degeneration of spinal muscles, rather than limb muscles, emerges as a key driver of gait dysfunction in dysferlinopathy, revealing axial muscle pathology as a previously overlooked disease feature and identifying GSK3 inhibition as a promising therapeutic strategy.