Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal

Jiang, Weihua; Zhu, Jing; Zhuang, Xun; Zhang, Xiping; Luo, Tao; Esser, Karyn A.; Ren, Hongmei

doi:10.1074/jbc.m115.686519

Cited by 27 publications

(33 citation statements)

References 55 publications

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“…Furthermore, insulin stimulated glucose uptake in skeletal muscle was suppressed by lipin-1 knockdown. Lipin-1 was reported to be up-regulated during C2C12 myoblast differentiation, and knockdown of lipin-1 expression by infection with adenovirus (sh Lpin1 ) before initiation of differentiation in C2C12 myoblast would suppress myogenic differentiation 33. However, in our study, lipin-1 silencing didn't change the protein expression of myogenin and MYH in C2C12 myotubes, suggested that the myoblast differentiation wasn't affected.…”

Section: Discussioncontrasting

confidence: 63%

Downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes

Huang¹,

Huang²,

Wang³

et al. 2017

Int. J. Biol. Sci.

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Dysregulation of lipid metabolism in skeletal muscle is involved in the development of insulin resistance. Mutations in lipin-1, a key lipid metabolism regulator leads to significant systemic insulin resistance in fld mice. However, the function of lipin-1 on lipid metabolism and insulin sensitivity in skeletal muscle is still unclear. Herein we demonstrated that downregulation of lipin-1 in C2C12 myotubes by siRNA transfection suppressed insulin action, characterized by reduced insulin stimulated Akt phosphorylation and glucose uptake. Correspondingly, decreased lipin-1 expression was observed in palmitate-induced insulin resistance in C2C12 myotubes, suggested that lipin-1 might play a role in the etiology of insulin resistance in skeletal muscle. The insulin resistance induced by lipin-1 downregulation was related to the disturbance of lipid homeostasis. Lipin-1 silencing reduced intracellular DAG and TAG levels, but elevated ceramide accumulation in C2C12 myotubes. Moreover, the impaired insulin stimulated Akt phosphorylation and glucose uptake caused by lipin-1 silencing could be blocked by the pretreatment with SPT inhibitor myriocin, ceramide synthase inhibitor FB1, or PP2A inhibitor okadaic acid, suggested that the increased ceramide accumulation might be responsible for the development of insulin resistance induced by lipin-1 silencing in C2C12 myotubes. Meanwhile, decreased lipin-1 expression also impaired mitochondrial function in C2C12 myotubes. Therefore, our study suggests that lipin-1 plays an important role in lipid metabolism and downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes. These results offer a molecular insight into the role of lipin-1 in the development of insulin resistance in skeletal muscle.

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Section: Discussioncontrasting

confidence: 63%

Downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes

Huang¹,

Huang²,

Wang³

et al. 2017

Int. J. Biol. Sci.

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“…This is consistent with a previous study in which we revealed that lipin1 is required for myoblast differentiation using lipin1 depleted myoblasts and primary myoblasts (Jiang et al . ).…”

Section: Resultsmentioning

confidence: 97%

“…Our earlier work in global lipin1‐deficient ( fld ) mice demonstrated that lipin1 plays a major role in SM regeneration (Jiang et al . ). In particular, fld mice exhibited smaller regenerated muscle fibre cross‐sectional areas in response to injury, accompanied by reduced MyoD expression compared to wild‐type (WT) mice.…”

Section: Introductionmentioning

confidence: 97%

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

Jama

Huang

Alshudukhi

et al. 2018

The Journal of Physiology

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Key points Lipin1 is critical for skeletal muscle development. Lipin1 regulates MyoD and myocyte‐specific enhancer factor 2C (MEF2c) expression via the protein kinase C (PKC)/histone deacetylase 5‐mediated pathway. Inhibition of PKCμ activity suppresses myoblast differentiation by inhibiting MyoD and MEF2c expression. Abstract Our previous characterization of global lipin1‐deficient (fld) mice demonstrated that lipin1 played a novel role in skeletal muscle (SM) regeneration. The present study using cell type‐specific Myf5‐cre;Lipin1fl/fl conditional knockout mice (Lipin1Myf5cKO) shows that lipin1 is a major determinant of SM development. Lipin1 deficiency induced reduced muscle mass and myopathy. Our results from lipin1‐deficient myoblasts suggested that lipin1 regulates myoblast differentiation via the protein kinase Cμ (PKCμ)/histone deacetylase 5 (HDAC5)/myocyte‐specific enhancer factor 2C (MEF2c):MyoD‐mediated pathway. Lipin1 deficiency leads to the suppression of PKC isoform activities, as well as inhibition of the downstream target of PKCμ, class II deacetylase HDAC5 nuclear export, and, consequently, inhibition of MEF2c and MyoD expression in the SM of lipin1Myf5cKO mice. Restoration of diacylglycerol‐mediated signalling in lipin1 deficient myoblasts by phorbol 12‐myristate 13‐acetate transiently activated PKC and HDAC5, and upregulated MEF2c expression. Our findings provide insights into the signalling circuitry that regulates SM development, and have important implications for developing intervention aimed at treating muscular dystrophy.

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“…Muscle from fld mice also exhibited evidence of myocyte turnover, with > 10% of myocytes representing newly differentiated cells, presumably replacing dead myocytes. Lipin 1 deficient mice also have impaired muscle regeneration in response to injury [123], which could contribute to the severe muscle pathology in mice and humans lacking lipin 1.…”

Section: Lipin Gene Mutations and Diseasementioning

confidence: 99%

Lipin proteins and glycerolipid metabolism: Roles at the ER membrane and beyond

Zhang

Reue

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

106

108

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The regulation of glycerolipid biosynthesis is critical for homeostasis of cellular lipid stores and membranes. Here we review the role of lipin phosphatidic acid phosphatase enzymes in glycerolipid synthesis. Lipin proteins are unique among glycerolipid biosynthetic enzymes in their ability to transit among cellular membranes, rather than remain membrane tethered. We focus on the mechanisms that underlie lipin protein interactions with membranes and the versatile roles of lipins in several organelles, including the endoplasmic reticulum, mitochondria, endolysosomes, lipid droplets, and nucleus. We also review the corresponding physiological roles of lipins, which have been uncovered by the study of genetic lipin deficiencies. We propose that the growing body of knowledge concerning the biochemical and cellular activities of lipin proteins will be valuable for understanding the physiological functions of lipin proteins in health and disease.

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Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal

Cited by 27 publications

References 55 publications

Downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes

Downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes

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

Lipin proteins and glycerolipid metabolism: Roles at the ER membrane and beyond

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