Fibrillin-Related Proteins Control Calcium Homeostasis in Dystrophic Muscle Across Species

Duchenne muscular dystrophy (DMD) involves progressive muscle degeneration associated with impaired calcium homeostasis, particularly defective calcium clearance during muscle relaxation. However, the mechanisms linking extracellular matrix (ECM) integrity to calcium regulation remain unclear. We investigated whether MUA-3 , a Caenorhabditis elegans fibrillin-related ECM protein, contributes to calcium dysregulation in dystrophic muscle. Using fluorescent calcium imaging in transgenic worms expressing muscle-specific GCaMP2, we found that mua-3 downregulation selectively elevated resting calcium levels in healthy muscle, phenocopying the dystrophic calcium signature. Critically, partial mua-3 downregulation had no additional effect in dystrophic ( dys-1 ) muscle, where mua-3 expression was already reduced by 57%, suggesting loss of mua-3 function contributes to dystrophic pathology. In human dystrophic myoblasts, we observed parallel findings: elevated sarcoplasmic calcium concurrent with significant downregulation of fibrillin genes FBN1/FBN2 . These findings identify fibrillin-related proteins as potential regulators of muscle calcium homeostasis across species and suggest that ECM-calcium coupling represents a conserved pathological mechanism in muscular dystrophy.