The biophysical environment of membrane phospholipids affects the structure, function, and stability of membrane-bound proteins1,2. Obesity can disrupt membrane lipids, and, in particular, alter the activity of sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) to affect cellular metabolism3,4,5. Recent evidence suggests that the transport efficiency (Ca2+ uptake and ATP hydrolysis) of skeletal muscle SERCA can be uncoupled to increase energy expenditure and protect mice from diet-induced obesity6,7. In isolated sarcoplasmic reticulum vesicles, membrane phospholipid composition is known to modulate SERCA efficiency8,9,10,11. Here we show that skeletal muscle sarcoplasmic reticulum phospholipids can be altered to decrease SERCA efficiency and increase the whole-body metabolic rate. The absence of skeletal muscle phosphatidylethanolamine methyltransferase (PEMT) promotes an increase in the skeletal muscle and whole-body metabolic rate to protect mice from diet-induced obesity. The elevation in metabolic rate is caused by a decrease in SERCA Ca2+-transport efficiency, whereas mitochondrial uncoupling is unaffected. Our findings support the hypothesis that skeletal muscle energy efficiency can be reduced to promote protection from obesity.
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Data that support the findings of this study are available from the corresponding author upon reasonable request.
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This research is supported by NIH DK107397, DK109888 (to K.F.), DK110656 (to P.D.N.), DK112826, DK108833 (to W.L.H.), DK115824, DK116450 (to S.A.S.), DK103930 (to C.J.V.), AR066660 (to E.E.S.), AR070200 (to J.J.B.), HL129362 (to T.E.R.), and DK091317 (to T.S.T.), P&F funding from P30 DK020579 at Washington University in St. Louis (to K.F.), American Heart Association 18PRE33960491 (to A.R.P.V.) and 19PRE34380991 (to J.M.J.), Larry H. & Gail Miller Family Foundation (to P.J.F. and C.J.V.), and Uehara Memorial Foundation (to H.E.). University of Utah Metabolomics Core Facility is supported by S10 OD016232, S10 OD021505, and U54 DK110858.
The authors declare no competing financial interests.
Peer review information Primary Handling Editor: Elena Bellafante.
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Verkerke, A.R.P., Ferrara, P.J., Lin, CT. et al. Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency. Nat Metab 1, 876–885 (2019). https://doi.org/10.1038/s42255-019-0111-2
Nature Metabolism (2019)