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

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 metabolism3–5. 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 efficiency8–11. 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. The role of skeletal muscle in non-shivering thermogenesis is not fully elucidated. Here the authors show that, in muscle, phospholipids can influence whole-body metabolic rate and counteract obesity by altering calcium signalling and inducing energy expenditure.