Mini-agrin prevents calcium leakage and restores the dystrophin complex
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Muscle cell death in muscular dystrophies depends upon calcium ion (Ca ++ ) leakage through sarcolemma and sarcoplasmic reticulum, triggered by muscle stretch during eccentric contraction.
We show here that Ca ++ spikes are detected in dystrophic myogenic cells in culture since early differentiation, before sarcomere assembly and contraction. Healthy and genetically corrected dystrophic myotubes do not display Ca ++ spikes which are blocked by co-culturing DMD myogenic cells with embryonic mouse motoneurons or treating them with agrin proteoglycan. Same effect is elicited by a muscle spliced, COOH peptide of agrin (termed here mini-agrin) that interacts with dystroglycan, favouring its binding to the basal lamina.
Lack of dystrophin in DMD myotubes results in decreased expression of Ca V 1.1 (CACNA1S), a Ca ++ sensor component of the Dihydropyridine Receptor (DHPR) complex, known to regulate Ryanodine Receptor 1 (RyR1). These events explain the emergence of Ca ++ spikes. Mini-agrin addition to medium, or lentivector-mediated mini-agrin expression in transplanted cells in vivo, stabilize the expression of Ca V 1.1 on the membrane. This leads to disappearance of Ca ++ spikes and to reappearance of α-dystroglycan, α-sarcoglycan and n-NOS, indicating the reconstitution of the dystrophin complex in the absence of dystrophin. These findings unveil a novel regulatory mechanism and offer a new therapeutic opportunity for targeting calcium ion influx as a co-treatment strategy.
