Biology subjects

Roseguini, B. T.

Publications and source records attributed to Roseguini, B. T..

2 recordsLinked to original sources

bioRxiv2022

PRMT5 links lipid metabolism to contractile function of skeletal muscles

The skeletal muscle plays a key role in systemic energy homeostasis besides its canonical contractile function, but what couples these functions is poorly defined. Protein Arginine MethylTransferase 5 (PRMT5) is a well-known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As adult muscles express high levels of Prmt5, we generated myocyte-specific Prmt5 knockout (Prmt5MKO) mice. We observed reduced muscle mass, oxidative capacity, force production and exercise performance in Prmt5MKO mice. The motor deficiency is associated with scarce lipid droplets in myofibers due to defects in lipid biosynthesis and degradation. First, Prmt5MKO reduced demethylation and stability of Sterol Regulatory Element-Binding Transcription Factor 1a (SREBP1a), a master regulator of de novo lipogenesis. Second, Prmt5MKO impaired the repressive H4R3Me2s (histone H4 arginine-3 symmetric demethylation) at the Pnpla2 gene, elevating the level of its encoded protein ATGL, the rate-limiting enzyme catalyzing lipolysis. Accordingly, myocyte-specific double knockout of Pnpla2 and Prmt5 normalized muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.

molecular biology↗

bioRxiv2020

PTEN Inhibition Ameliorates Muscle Degeneration and Improves Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is caused by mutation of the muscle membrane protein dystrophin and characterized by severe degeneration of myofibers, progressive muscle wasting and loss of mobility, ultimately cardiorespiratory failure and premature death. Here we report that skeletal muscle-specific knockout (KO) of Phosphatase and tensin homolog (Pten) gene in an animal model of DMD (mdx mice) alleviates myofiber degeneration and restores muscle function without increasing tumor incidences. Specifically, Pten KO normalizes myofiber size and prevents muscular atrophy, and improves grip strength and exercise performance of mdx mice. Pten KO also reduces fibrosis and inflammation; and ameliorates muscle pathology in mdx mice. Moreover, we found that Pten KO upregulates extracellular matrix and basement membrane components positively correlated to wound healing, but suppresses negative regulators of wound healing and lipid biosynthesis; and restores the integrity of muscle basement membrane in mdx mice. Importantly, pharmacological inhibition of PTEN similarly ameliorates muscle pathology and improves muscle integrity and function in mdx mice. Our finding provides evidence that PTEN inhibition may represent a potential therapeutic strategy to restore muscle function in DMD.

developmental biology↗