{Reference Type}: Journal Article
{Title}: Exploring lipin1 as a promising therapeutic target for the treatment of Duchenne muscular dystrophy.
{Author}: Jama A;Alshudukhi AA;Burke S;Dong L;Kamau JK;Morris B;Alkhomsi IA;Finck BN;Voss AA;Ren H;
{Journal}: J Transl Med
{Volume}: 22
{Issue}: 1
{Year}: 2024 Jul 16
{Factor}: 8.44
{DOI}: 10.1186/s12967-024-05494-z
{Abstract}: <B>BACKGROUND: </B>Duchenne muscular dystrophy (DMD) is a progressive and devastating muscle disease, resulting from the absence of dystrophin. This leads to cell membrane instability, susceptibility to contraction-induced muscle damage, subsequent muscle degeneration, and eventually disability and early death of patients. Currently, there is no cure for DMD. Our recent studies identified that lipin1 plays a critical role in maintaining myofiber stability and integrity. However, lipin1 gene expression levels are dramatically reduced in the skeletal muscles of DMD patients and mdx mice.<BR><B>METHODS: </B>To identify whether increased lipin1 expression could prevent dystrophic pathology, we employed unique muscle-specific mdx:lipin1 transgenic (mdx:lipin1Tg/0) mice in which lipin1 was restored in the dystrophic muscle of mdx mice, intramuscular gene delivery, as well as cell culture system.<BR><B>RESULTS: </B>We found that increased lipin1 expression suppressed muscle degeneration and inflammation, reduced fibrosis, strengthened membrane integrity, and resulted in improved muscle contractile and lengthening force, and muscle performance in mdx:lipin1Tg/0 compared to mdx mice. To confirm the role of lipin1 in dystrophic muscle, we then administered AAV1-lipin1 via intramuscular injection in mdx mice. Consistently, lipin1 restoration inhibited myofiber necroptosis and lessened muscle degeneration. Using a cell culture system, we further found that differentiated primary mdx myoblasts had elevated expression levels of necroptotic markers and medium creatine kinase (CK), which could be a result of sarcolemmal damage. Most importantly, increased lipin1 expression levels in differentiated myoblasts from mdx:lipin1Tg/0 mice substantially inhibited the elevation of necroptotic markers and medium CK levels.<BR><B>CONCLUSIONS: </B>Overall, our data suggest that lipin1 is a promising therapeutic target for the treatment of dystrophic muscles.