Lipin1 plays complementary roles in myofibre stability and regeneration in dystrophic muscles

Abstract

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by dystrophin mutations, leading to the loss of sarcolemmal integrity, and resulting in progressive myofibre necrosis and impaired muscle function. Our previous studies suggest that lipin1 is important for skeletal muscle regeneration and myofibre integrity. Additionally, we discovered that mRNA expression levels of lipin1 were significantly reduced in skeletal muscle of DMD patients and the mdx mouse model. To understand the role of lipin1 in dystrophic muscle, we generated dystrophin/lipin1 double knockout (DKO) mice, and compared the limb muscle pathology and function of wild‐type B10, muscle‐specific lipin1 deficient (lipin1Myf5cKO), mdx and DKO mice. We found that further knockout of lipin1 in dystrophic muscle exhibited a more severe phenotype characterized by increased necroptosis, fibrosis and exacerbated membrane damage in DKO compared to mdx mice. In barium chloride‐induced muscle injury, both lipin1Myf5cKO and DKO showed prolonged regeneration at day 14 post‐injection, suggesting that lipin1 is critical for muscle regeneration. In situ contractile function assays showed that lipin1 deficiency in dystrophic muscle led to reduced specific force production. Using a cell culture system, we found that lipin1 deficiency led to elevated expression levels of necroptotic markers and medium creatine kinase, which could be a result of sarcolemmal damage. Most importantly, restoration of lipin1 inhibited the elevation of necroptotic markers in differentiated primary lipin1‐deficient myoblasts. Overall, our data suggests that lipin1 plays complementary roles in myofibre stability and muscle function in dystrophic muscles, and overexpression of lipin1 may serve as a potential therapeutic strategy for dystrophic muscles. Key points We identified that lipin1 mRNA expression levels are significantly reduced in skeletal muscles of Duchenne muscular dystrophy patients and mdx mice. We found that further depletion of lipin1 in skeletal muscles of mdx mice induces more severe dystrophic phenotypes, including enhanced myofibre sarcolemma damage, muscle necroptosis, inflammation, fibrosis and reduced specific force production. Lipin1 deficiency leads to elevated expression levels of necroptotic markers, whereas restoration of lipin1 inhibits their expression. Our results suggest that lipin1 is functionally complementary to dystrophin in muscle membrane integrity and muscle regeneration.

Glucocorticoid intermittence coordinates rescue of energy and mass in aging-related sarcopenia through the myocyte-autonomous PGC1alpha-Lipin1 transactivation

“…This provides an intriguing new context for the understudied Lipin1 property as PGC1alpha co-activator, which was investigated until now only in liver 19 . Considering the recent findings with Lipin1 ablation and complex lipid metabolism in heart 48 , future studies are warranted in better identifying how Lipin1 regulates lipotoxicity in the sarcopenic muscle, particularly in light of the recent complex role reported for Lipin1 in counteracting dystrophic pathophysiology 20 .…”

“…Lipin1 acts in the cytosol as a phosphatidic acid phosphohydrolase 17,18 and in the nucleus as a regulator of gene transcription 19 . In muscle, Lipin1 regulates many complex processes, including myofiber stability and regeneration 20 , as well as autophagy/mitophagy 21,22 . In hepatocytes, Lipin1 co-activates PGC1alpha through a direct protein-protein interaction 19 , but this role of Lipin1 remains unexplored in muscle.…”

Automated Image Analysis Pipeline Development to Monitor Disease Progression in Muscular Dystrophy Using Cell Profiler

“…EBD dye injection was performed as we did previously [ 16 , 17 ]. Briefly, mice were injected with EBD (10mg/ml stock in sterile saline, 0.1ml/10g body weight) I.P.…”

Research Trends in C-Terminal Domain Nuclear Envelope Phosphatase 1

“…Human LIPIN1 is the ortholog to PAH1 in yeast. It acts as a PA phosphatase and is also one of the critical regulators of cellular lipid metabolism in nuclear membrane biogenesis and various tissues [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Polymorphism in LIPIN isoforms may lead to a poor condition.…”