Loss of Lipin1 Contributes to Multiple Pathological Processes in the Development of Heart Failure

Background Lipin1 has dual functions acting as phosphatidic acid phosphatase required for lipid synthesis and as a transcriptional coactivator. Our previous research demonstrated that lipin1 is critical for maintaining sarcolemmal integrity in skeletal muscle. Given the importance of sarcolemmal stability for cardiac muscle viability and function, we investigated the role of lipin1 in the heart using a novel cardiac‐specific lipin1 deficient ( Myh6‐lipin1 −/− ) mouse model. Methods We characterized male Myh6‐lipin1 −/− mice at 3 to 4 months of age to assess cardiac structure and function. Results Myh6‐lipin1 −/− mice exhibited marked cardiac inflammation, fibrosis, increased expression of cell death markers, and elevated sarcolemmal damage. Lipin1 deficiency led to disrupted sarcolemmal integrity, evidenced by decreased expression and mislocalization of key membrane structural proteins. Upon isoproterenol‐induced cardiac stress, lipin1‐deficient mice demonstrated significantly greater reductions in ejection fraction and fractional shortening compared with control mice. Conclusions These findings reveal a critical role for lipin1 in maintaining cardiac sarcolemmal integrity and emphasize its importance in supporting normal cardiac morphology and function, particularly under stress conditions.