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.-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. Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice.

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone‐responsive myopathy

“…The defect in PAP1 activity is expected to shift the balance toward an accumulation of PA to the detriment of diacylglycerol (DAG) levels (Han et al, 2007;Reue, 2007). However, we reveal both PA and DAG accumulation in mutant muscles (Fig 3), consistent with a recent report (Schweitzer et al, 2018). Since DAG is a precursor of both phospholipids and TAG, our data explain the increase in both lipid species.…”

Lipin1 is required for skeletal muscle development by regulating MEF2c and MyoD expression

“…1D-E). Consistent with recent reports in skeletal muscle-specific lipin1 deficient (MCK promoter)(Schweitzer et al 2018) and fld(Zhang et al 2014) Lipin1 deficiency in Myf5-expressing cells results in reduced SM mass Appearance of TA and GAS muscles in WT and Lipin1 Myf5cKO mice at 3 months of age (TA and GAS are indicated by arrows) (A). Isolated TA and GAS muscle (B) and the muscle weight (C) in WT and Lipin1 Myf5cKO mice.…”

“…Consistent with recent reports in skeletal muscle‐specific lipin1 deficient (MCK promoter) (Schweitzer et al . ) and fld (Zhang et al . ) mice, SM of Lipin1 Myf5cKO mice also displayed a large number of centrally nucleated fibres compared to control mice, suggesting that lipin1 deficiency results in myopathy.…”

“…; Schweitzer et al . ). There are three mammalian lipin genes, lipin1, lipin2 and lipin3, with distinct but partially overlapping expression pattern (Donkor et al .…”

“…Lipin1 catalyses the penultimate step in triglyceride synthesis and acts as a nuclear transcriptional coactivator (Finck et al 2006;Han et al 2006;Kim et al 2013). Studies of lipin1 have revealed multiple roles: its lipid-storing function in adipose tissue, its role in Schwann cell and macrophage biology and its role in hepatic lipid metabolism (Rehnmark et al 1998;Finck et al 2006;Nadra et al 2008;Reue & Dwyer, 2009;Ren et al 2010;Nadra et al 2012;Hu et al 2013;Kim et al 2013;Mitra et al 2013;Schweitzer et al 2015;Wang et al 2016;Vozenilek et al 2018), as well as new roles in autophagy and mitophagy in other recent studies (Zhang et al 2014;Alshudukhi et al 2018;Schweitzer et al 2018). There are three mammalian lipin genes, lipin1, lipin2 and lipin3, with distinct but partially overlapping expression pattern (Donkor et al 2007), although lipin1 is the predominant lipin isoform in skeletal muscle (SM), accounting for almost all phosphatidic acid phosphatase activity in SM (Han et al 2006;Reue & Dwyer, 2009).…”