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PRMT5 links lipid metabolism to contractile function of skeletal muscles
Skeletal muscle plays a key role in systemic energy homeostasis besides its contractile function, but what links these functions is poorly defined. Protein Arginine Methyl Transferase 5 (PRMT5) is a well‐known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As...
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Published in: | EMBO reports 2023-08, Vol.24 (8), p.e57306-n/a |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Skeletal muscle plays a key role in systemic energy homeostasis besides its contractile function, but what links these functions is poorly defined. Protein Arginine Methyl Transferase 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 skeletal muscle‐specific Prmt5 knockout (Prmt5MKO) mice. We observe 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 accelerated degradation. Specifically, PRMT5 deletion reduces dimethylation and stability of Sterol Regulatory Element‐Binding Transcription Factor 1a (SREBP1a), a master regulator of de novo lipogenesis. Moreover, Prmt5MKO impairs the repressive H4R3 symmetric dimethylation at the Pnpla2 promoter, elevating the level of its encoded protein ATGL, the rate‐limiting enzyme catalyzing lipolysis. Accordingly, skeletal muscle‐specific double knockout of Pnpla2 and Prmt5 normalizes muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.
Synopsis
PRMT5 contributes to maintain overall energy homeostasis in skeletal muscle, and depletion of PRMT5 leads to a decline in muscle mass and functionality.
Reduction of PRMT5 in skeletal muscles leads to impaired muscle contraction.
Loss of PRMT5 results in the formation of atrophied myotubes lacking lipid droplets.
PRMT5 catalyzes methylation of SREBP1 to promote lipogenesis.
PRMT5 increases the repressive H4R3Me2s modification to suppress Pnpla2 (ATGL) gene expression and lipolysis.
PRMT5 contributes to maintain overall energy homeostasis in skeletal muscle, and depletion of PRMT5 leads to a decline in muscle mass and functionality. |
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ISSN: | 1469-221X 1469-3178 |
DOI: | 10.15252/embr.202357306 |