Duchenne Muscular Dystrophy (DMD) stands as a debilitating condition triggered by mutations in the dystrophin gene. These mutations culminate in compromised sarcolemmal integrity, initiating a cascade of events marked by progressive myofibre necrosis and deteriorated muscle function. Earlier investigations from our lab underscored the significance of lipin1 in bolstering skeletal muscle regeneration and upholding myofibre integrity. Moreover, our studies unveiled a substantial reduction in lipin1 mRNA expression within the skeletal muscle of both DMD patients and the mdx mouse model, a classic model for DMD. Seeking a deeper comprehension of lipin1's role in dystrophic muscle, we embarked on generating dystrophin/lipin1 Double Knockout (DKO) mice. Through a comparative analysis encompassing wild-type B10 mice, muscle-specific lipin1 deficient (lipin1Myf5cKO) mice, mdx mice, and DKO mice, we uncovered a more severe phenotype in the DKO cohort, characterized by intensified necroptosis, fibrosis, and aggravated membrane damage relative to mdx mice. Intriguingly, barium chloride-induced muscle injury spotlighted prolonged regeneration at day 14 post-injection in both lipin1Myf5cKO and DKO mice, underscoring the critical role of lipin1 in muscle regeneration. In situ contractile function assays disclosed diminished specific force production in dystrophic muscles lacking lipin1. Cellular experimentation further solidified these findings, as lipin1-deficient cells exhibited elevated levels of necroptotic markers and medium creatine kinase, potentially stemming from sarcolemmal damage. Significantly, the restoration of lipin1 curbed the elevation of necroptotic markers in differentiated primary lipin1-deficient myoblasts. Collectively, our findings paint a picture of lipin1's dual contribution to myofibre stability and muscle function within the realm of dystrophic muscles. The tantalizing prospect of leveraging lipin1 overexpression as a therapeutic strategy for dystrophic muscles beckons as a beacon of hope.
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