Phospholipid methylation regulates muscle metabolic rate through Ca(2+) transport efficiency

The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins.(1,2) Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca(2+)-ATPase (SERCA) to affect cellular metabolism.(3–5) Recent evidence suggests that transport efficiency (Ca(2+) uptake / ATP hydrolysis) of skeletal muscle SERCA can be uncoupled to increase energy expenditure and protect mice from diet-induced obesity.(6,7) In isolated SR vesicles, membrane phospholipid composition is known to modulate SERCA efficiency.(8–11) Here we show that skeletal muscle SR phospholipids can be altered to decrease SERCA efficiency and increase whole-body metabolic rate. The absence of skeletal muscle phosphatidylethanolamine (PE) methyltransferase (PEMT) promotes an increase in 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 Ca(2+)-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.