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bioRxiv · 10.1101/2025.06.09.658655

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

Marchiafava, D.·Vidal-Gadea, A. G.
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Abstract

Duchenne muscular dystrophy (DMD) involves progressive muscle degeneration associated with calcium dysregulation, but the mechanisms linking extracellular matrix (ECM) integrity to calcium homeostasis remain unclear. We investigated whether MUA- 3, a fibrillin-related ECM protein in Caenorhabditis elegans, contributes to calcium regulation in dystrophic muscle. Using fluorescent calcium imaging in transgenic worms expressing muscle-specific GCaMP2, we found that downregulating mua-3 selectively elevated resting calcium levels in healthy muscle but had no effect in dystrophic (dys-1) muscle, suggesting impaired MUA-3 function in dystrophy. Despite altered calcium dynamics, mua-3 downregulation did not affect locomotor function. In human dystrophic myoblasts, we observed significantly elevated sarcoplasmic calcium levels concurrent with substantial downregulation of fibrillin genes FBN1/FBN2. These findings demonstrate that fibrillin-related proteins regulate calcium homeostasis across species, suggesting that ECM integrity directly contributes to cellular calcium control in muscle. This work identifies a conserved mechanism linking extracellular matrix stability to intracellular calcium regulation and suggests that targeting ECM-calcium coupling may offer new therapeutic approaches for muscular dystrophy.

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Marchiafava, D., Vidal-Gadea, A. G.. 2025-06-11. Fibrillin-Related Proteins Control Calcium Homeostasis in Dystrophic Muscle Across Species. https://doi.org/10.1101/2025.06.09.658655

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