Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency

The biophysical environment of membrane phospholipids affects the 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 Ca2+-ATPase (SERCA) to affect cellular metabolism(3-5). 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 obesity(6,7). In isolated sarcoplasmic reticulum vesicles, membrane phospholipid composition is known to modulate SERCA efficiency(8-11). 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.