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Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency

Nature Metabolism volume 1, pages 876–885 (2019)Cite this article

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Abstract

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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Fig. 1: PEMTKO mice exhibit increased muscle metabolic rate and are protected from diet-induced obesity.
Fig. 2: Ca2+ transport inefficiency explains the increased muscle metabolic rate in PEMTKO muscle.
Fig. 3: PEMT-MKO mice are protected from diet-induced obesity.
Fig. 4: Skeletal muscle PEMT alters SR phospholipids to regulate muscle oxygen consumption.

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Data availability

Data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

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.

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Authors and Affiliations

  1. Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, UT, USA

    Anthony R. P. Verkerke, Patrick J. Ferrara, Jordan M. Johnson, Hiroaki Eshima, Piyarat Siripoksup, Trevor S. Tippetts, Claudio J. Villanueva, Scott A. Summers, William L. Holland, James E. Cox & Katsuhiko Funai

  2. Department of Nutrition & Integrative Physiology, University of Utah, Salt Lake City, UT, USA

    Anthony R. P. Verkerke, Patrick J. Ferrara, Jordan M. Johnson, Trevor S. Tippetts, Scott A. Summers, William L. Holland & Katsuhiko Funai

  3. East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA

    Chien-Te Lin, Christopher W. Paran, Brenton T. Laing, Edward J. Wentzler, Hu Huang, Espen E. Spangenburg, Jeffrey J. Brault, P. Darrell Neufer & Katsuhiko Funai

  4. Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA

    Terence E. Ryan

  5. Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT, USA

    J. Alan Maschek & James E. Cox

  6. Department of Physical Therapy & Athletic Training, University of Utah, Salt Lake City, UT, USA

    Piyarat Siripoksup & Katsuhiko Funai

  7. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA

    Claudio J. Villanueva & James E. Cox

  8. Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA

    Scott A. Summers, William L. Holland & Katsuhiko Funai

  9. Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada

    Dennis E. Vance

Authors
  1. Anthony R. P. Verkerke
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Contributions

A.R.P.V. and K.F. designed the study and wrote the manuscript. A.R.P.V. performed all metabolic phenotyping and biochemical assays. A.R.P.V., P.J.F., and E.E.S. performed muscle oxygen consumption assays. C.-T.L., J.M.J., T.E.R., and P.D.N. performed mitochondrial phenotyping. H.E. and P.S. assisted in muscle histology and functional measurements. C.J.V. assisted in experiments with adipose tissues. T.S.T., S.A.S., and W.L.H. assisted in AAV experiments. J.A.M. and J.E.C. performed mass spectrometry analyses. A.R.P.V. and J.J.B performed ultra-performance liquid chromatography. B.T.L and H.H. performed analyses on hypothalamus. A.R.P.V., C.W.P., E.J.W., D.E.V., and K.F. designed and generated the mouse models. T.E.R., H.H., E.E.S., J.J.B., S.A.S., W.L.H., J.E.C., D.E.V., and P.D.N. edited the manuscript.

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Correspondence to Katsuhiko Funai.

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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

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