Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice
George G. Schweitzer, Sara L. Collier, Zhouji Chen, Kyle S. McCommis, Sara K. Pittman, Jun Yoshino, Scot J. Matkovich, Fong Fu Hsu, Roman Chrast, James M. Eaton, Thurl E. Harris, Conrad C. Weihl, Brian N. Finck
Center of Regenerative Medicine
Bursky Center for Human Immunology & Immunotherapy Programs (CHiiPs)
Division of Endocrinology, Metabolism & Lipid Research
Division of Neuromuscular Medicine
Division of Geriatrics & Nutritional Science
DBBS - Molecular Cell Biology
DBBS - Neurosciences
Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride-synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole-body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle-specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.
https://doi.org/10.1096/fj.201800361R
Diacylglycerol
LPIN1
Triacylglycerol
10.1096/fj.201800361R
Dive into the research topics of 'Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice'. Together they form a unique fingerprint.
lipine Medicine & Life Sciences 100%
Phosphatidate Phosphatase Medicine & Life Sciences 92%
Phosphatidic Acid Chemical Compounds 73%
Muscular Diseases Medicine & Life Sciences 62%
Muscles Medicine & Life Sciences 34%
Glycerolipid Chemical Compounds 21%
Creatine Chemical Compounds 18%
Muscle Cells Medicine & Life Sciences 15%
Schweitzer, G. G., Collier, S. L., Chen, Z., McCommis, K. S., Pittman, S. K., Yoshino, J., Matkovich, S. J., Hsu, F. F., Chrast, R., Eaton, J. M., Harris, T. E., Weihl, C. C., & Finck, B. N. (2019). Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. FASEB Journal, 33(1), 652-667. https://doi.org/10.1096/fj.201800361R
Schweitzer, George G. ; Collier, Sara L. ; Chen, Zhouji et al. / Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. In: FASEB Journal. 2019 ; Vol. 33, No. 1. pp. 652-667.
@article{cd90f77c9ea94458b8fe2efb854e0127,
title = "Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice",
abstract = "Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride-synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole-body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle-specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.",
keywords = "Autophagy, Diacylglycerol, LPIN1, Rhabdomyolysis, Triacylglycerol",
author = "Schweitzer, {George G.} and Collier, {Sara L.} and Zhouji Chen and McCommis, {Kyle S.} and Pittman, {Sara K.} and Jun Yoshino and Matkovich, {Scot J.} and Hsu, {Fong Fu} and Roman Chrast and Eaton, {James M.} and Harris, {Thurl E.} and Weihl, {Conrad C.} and Finck, {Brian N.}",
note = "Funding Information: The authors thank Dr. Alan Pestronk and Dr. Abhinav Diwan for technical assistance in interpreting histology, and Dennis J. Dietzen for determining plasma creatine kinase (all from Washington University). This work was supported by U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK078187 and NIH National Heart, Lung, and Blood Institute Grant R01 HL119225 (to B.N.F.). G.G.S. was supported by NIH National Heart, Lung, and Blood Institute Grants T32 HL007275, T32 HL007081, and the Washington University Institute of Clinical and Translational Sciences NIH Grant UL1 TR000448, Subaward KL2 TR000450, from the National Center for Advancing Translational Sciences (NCATS). K.S.M. was supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases Grant T32-DK007120. J.Y. was supported by Washington University Institute of Clinical and Translational Sciences NIH Grant UL1 TR000448, Subaward KL2 TR000450. T.E.H. and J.M.E. were supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK101946. C.C.W. and S.K.P were supported by NIH National Institute on Aging Grant R01 AG031867. This work was also supported by the cores of the Washington University Nutrition Obesity Research Center (Grant P30 DK56341), Diabetes Research Center (DRC) (Grant P30 DK020579), the Metabolomics Facility at Washington University (Grant P30 DK056341), and the Washington University NIH National Institute of General Medical Sciences Biomedical Mass Spectrometry Resource (Grant P41 GM103422) to F.-F.H.; the Washington University Genome Technology Access Center in the Department of Genetics (Grant P30 CA91842); and the Department of Pathology DRC Electron Microscopy Facility (Grant P60 DK020579). The authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} FASEB.",
doi = "10.1096/fj.201800361R",
Schweitzer, GG, Collier, SL, Chen, Z, McCommis, KS, Pittman, SK, Yoshino, J, Matkovich, SJ, Hsu, FF, Chrast, R, Eaton, JM, Harris, TE, Weihl, CC & Finck, BN 2019, 'Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice', FASEB Journal, vol. 33, no. 1, pp. 652-667. https://doi.org/10.1096/fj.201800361R
Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. / Schweitzer, George G.; Collier, Sara L.; Chen, Zhouji et al.
In: FASEB Journal, Vol. 33, No. 1, 01.2019, p. 652-667.
T1 - Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice
AU - Schweitzer, George G.
AU - Collier, Sara L.
AU - Chen, Zhouji
AU - McCommis, Kyle S.
AU - Pittman, Sara K.
AU - Yoshino, Jun
AU - Matkovich, Scot J.
AU - Hsu, Fong Fu
AU - Chrast, Roman
AU - Eaton, James M.
AU - Harris, Thurl E.
AU - Weihl, Conrad C.
AU - Finck, Brian N.
N1 - Funding Information: The authors thank Dr. Alan Pestronk and Dr. Abhinav Diwan for technical assistance in interpreting histology, and Dennis J. Dietzen for determining plasma creatine kinase (all from Washington University). This work was supported by U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK078187 and NIH National Heart, Lung, and Blood Institute Grant R01 HL119225 (to B.N.F.). G.G.S. was supported by NIH National Heart, Lung, and Blood Institute Grants T32 HL007275, T32 HL007081, and the Washington University Institute of Clinical and Translational Sciences NIH Grant UL1 TR000448, Subaward KL2 TR000450, from the National Center for Advancing Translational Sciences (NCATS). K.S.M. was supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases Grant T32-DK007120. J.Y. was supported by Washington University Institute of Clinical and Translational Sciences NIH Grant UL1 TR000448, Subaward KL2 TR000450. T.E.H. and J.M.E. were supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK101946. C.C.W. and S.K.P were supported by NIH National Institute on Aging Grant R01 AG031867. This work was also supported by the cores of the Washington University Nutrition Obesity Research Center (Grant P30 DK56341), Diabetes Research Center (DRC) (Grant P30 DK020579), the Metabolomics Facility at Washington University (Grant P30 DK056341), and the Washington University NIH National Institute of General Medical Sciences Biomedical Mass Spectrometry Resource (Grant P41 GM103422) to F.-F.H.; the Washington University Genome Technology Access Center in the Department of Genetics (Grant P30 CA91842); and the Department of Pathology DRC Electron Microscopy Facility (Grant P60 DK020579). The authors declare no conflicts of interest. Publisher Copyright: © FASEB.
N2 - Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride-synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole-body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle-specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.
AB - Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride-synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole-body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle-specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.
KW - Autophagy
KW - Diacylglycerol
KW - LPIN1
KW - Rhabdomyolysis
KW - Triacylglycerol
U2 - 10.1096/fj.201800361R
DO - 10.1096/fj.201800361R
Schweitzer GG, Collier SL, Chen Z, McCommis KS, Pittman SK, Yoshino J et al. Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. FASEB Journal. 2019 Jan;33(1):652-667. doi: 10.1096/fj.201800361R