The CDP-ethanolamine pathway regulates skeletal muscle diacylglycerol content and mitochondrial biogenesis without altering insulin sensitivity

Ahrathy Selathurai, Greg M Kowalski, Micah L Burch, Patricio V Sepulveda, Steve Risis, Robert S Lee-Young, Severine Lamon, Peter J Meikle, Amanda J Genders, Sean L McGee, Matthew J Watt, Aaron Paul Russell, Matthew Frank, Suzanne Jackowski, Mark A Febbraio, Clinton R Bruce

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.
Original languageEnglish
Pages (from-to)718 - 730
Number of pages13
JournalCell Metabolism
Volume21
Issue number5
DOIs
Publication statusPublished - 2015

Cite this

Selathurai, A., Kowalski, G. M., Burch, M. L., Sepulveda, P. V., Risis, S., Lee-Young, R. S., ... Bruce, C. R. (2015). The CDP-ethanolamine pathway regulates skeletal muscle diacylglycerol content and mitochondrial biogenesis without altering insulin sensitivity. Cell Metabolism, 21(5), 718 - 730. https://doi.org/10.1016/j.cmet.2015.04.001
Selathurai, Ahrathy ; Kowalski, Greg M ; Burch, Micah L ; Sepulveda, Patricio V ; Risis, Steve ; Lee-Young, Robert S ; Lamon, Severine ; Meikle, Peter J ; Genders, Amanda J ; McGee, Sean L ; Watt, Matthew J ; Russell, Aaron Paul ; Frank, Matthew ; Jackowski, Suzanne ; Febbraio, Mark A ; Bruce, Clinton R. / The CDP-ethanolamine pathway regulates skeletal muscle diacylglycerol content and mitochondrial biogenesis without altering insulin sensitivity. In: Cell Metabolism. 2015 ; Vol. 21, No. 5. pp. 718 - 730.
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abstract = "Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.",
author = "Ahrathy Selathurai and Kowalski, {Greg M} and Burch, {Micah L} and Sepulveda, {Patricio V} and Steve Risis and Lee-Young, {Robert S} and Severine Lamon and Meikle, {Peter J} and Genders, {Amanda J} and McGee, {Sean L} and Watt, {Matthew J} and Russell, {Aaron Paul} and Matthew Frank and Suzanne Jackowski and Febbraio, {Mark A} and Bruce, {Clinton R}",
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Selathurai, A, Kowalski, GM, Burch, ML, Sepulveda, PV, Risis, S, Lee-Young, RS, Lamon, S, Meikle, PJ, Genders, AJ, McGee, SL, Watt, MJ, Russell, AP, Frank, M, Jackowski, S, Febbraio, MA & Bruce, CR 2015, 'The CDP-ethanolamine pathway regulates skeletal muscle diacylglycerol content and mitochondrial biogenesis without altering insulin sensitivity' Cell Metabolism, vol. 21, no. 5, pp. 718 - 730. https://doi.org/10.1016/j.cmet.2015.04.001

The CDP-ethanolamine pathway regulates skeletal muscle diacylglycerol content and mitochondrial biogenesis without altering insulin sensitivity. / Selathurai, Ahrathy; Kowalski, Greg M; Burch, Micah L; Sepulveda, Patricio V; Risis, Steve; Lee-Young, Robert S; Lamon, Severine; Meikle, Peter J; Genders, Amanda J; McGee, Sean L; Watt, Matthew J; Russell, Aaron Paul; Frank, Matthew; Jackowski, Suzanne; Febbraio, Mark A; Bruce, Clinton R.

In: Cell Metabolism, Vol. 21, No. 5, 2015, p. 718 - 730.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The CDP-ethanolamine pathway regulates skeletal muscle diacylglycerol content and mitochondrial biogenesis without altering insulin sensitivity

AU - Selathurai, Ahrathy

AU - Kowalski, Greg M

AU - Burch, Micah L

AU - Sepulveda, Patricio V

AU - Risis, Steve

AU - Lee-Young, Robert S

AU - Lamon, Severine

AU - Meikle, Peter J

AU - Genders, Amanda J

AU - McGee, Sean L

AU - Watt, Matthew J

AU - Russell, Aaron Paul

AU - Frank, Matthew

AU - Jackowski, Suzanne

AU - Febbraio, Mark A

AU - Bruce, Clinton R

PY - 2015

Y1 - 2015

N2 - Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.

AB - Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.

UR - http://www.sciencedirect.com/science/article/pii/S1550413115001564

U2 - 10.1016/j.cmet.2015.04.001

DO - 10.1016/j.cmet.2015.04.001

M3 - Article

VL - 21

SP - 718

EP - 730

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 5

ER -