Chambers 2021 JCI Insight

From Bioblast
Publications in the MiPMap
Chambers KT, Cooper MA, Swearingen AR, Brookheart RT, Schweitzer GG, Weinheimer CJ, Kovacs A, Koves TR, Muoio DM, McCommis KS, Finck BN (2021) Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations. JCI Insight 6:134340.

Β» PMID: 33986192 Open Access

Chambers Kari T, Cooper Michael A, Swearingen Alison R, Brookheart Rita T, Schweitzer George G, Weinheimer Carla J, Kovacs Attila, Koves Timothy R, Muoio Deborah M, McCommis Kyle S, Finck Brian N (2021) JCI Insight

Abstract: 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. β€’ Keywords: Cardiology, Cardiovascular disease, Intermediary metabolism, Metabolism, Mitochondria β€’ Bioblast editor: Reiswig R β€’ O2k-Network Lab: US NC Durham Koves TR, US MO St Louis McCommis KS

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart  Preparation: Permeabilized tissue  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS, ET  Pathway: F, N, S  HRR: Oxygraph-2k 


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