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Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations.

Publication ,  Journal Article
Chambers, KT; Cooper, MA; Swearingen, AR; Brookheart, RT; Schweitzer, GG; Weinheimer, CJ; Kovacs, A; Koves, TR; Muoio, DM; McCommis, KS; Finck, BN
Published in: JCI Insight
May 10, 2021

Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

May 10, 2021

Volume

6

Issue

9

Location

United States

Related Subject Headings

  • Triglycerides
  • Succinic Acid
  • Pyruvic Acid
  • Phosphatidic Acids
  • Phosphatidate Phosphatase
  • Myocardium
  • Myocardial Contraction
  • Mitochondria, Heart
  • Mice, Knockout
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
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Chambers, K. T., Cooper, M. A., Swearingen, A. R., Brookheart, R. T., Schweitzer, G. G., Weinheimer, C. J., … Finck, B. N. (2021). Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations. JCI Insight, 6(9). https://doi.org/10.1172/jci.insight.134340
Chambers, Kari T., Michael A. Cooper, Alison R. Swearingen, Rita T. Brookheart, George G. Schweitzer, Carla J. Weinheimer, Attila Kovacs, et al. “Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations.JCI Insight 6, no. 9 (May 10, 2021). https://doi.org/10.1172/jci.insight.134340.
Chambers KT, Cooper MA, Swearingen AR, Brookheart RT, Schweitzer GG, Weinheimer CJ, et al. Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations. JCI Insight. 2021 May 10;6(9).
Chambers, Kari T., et al. “Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations.JCI Insight, vol. 6, no. 9, May 2021. Pubmed, doi:10.1172/jci.insight.134340.
Chambers KT, Cooper MA, Swearingen AR, Brookheart RT, Schweitzer GG, Weinheimer CJ, Kovacs A, Koves TR, Muoio DM, McCommis KS, Finck BN. Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations. JCI Insight. 2021 May 10;6(9).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

May 10, 2021

Volume

6

Issue

9

Location

United States

Related Subject Headings

  • Triglycerides
  • Succinic Acid
  • Pyruvic Acid
  • Phosphatidic Acids
  • Phosphatidate Phosphatase
  • Myocardium
  • Myocardial Contraction
  • Mitochondria, Heart
  • Mice, Knockout
  • Mice