Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency

Nat Metab. 2019 Sep;1(9):876-885. doi: 10.1038/s42255-019-0111-2. Epub 2019 Sep 16.

Abstract

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) Ca2+-ATPase (SERCA) to affect cellular metabolism.3-5 Recent evidence suggests that transport efficiency (Ca2+ 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 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.

Publication types

  • Letter
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Diet, High-Fat
  • Energy Metabolism*
  • Ion Transport
  • Methylation
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Obesity / enzymology
  • Obesity / genetics
  • Phosphatidylethanolamine N-Methyltransferase / genetics
  • Phosphatidylethanolamine N-Methyltransferase / metabolism
  • Phospholipids / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism

Substances

  • Phospholipids
  • Phosphatidylethanolamine N-Methyltransferase
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium