title: Lipogenesis mitigates dysregulated sarcoplasmic reticulum calcium uptake in muscular dystrophy.
abstract: Muscular dystrophy is accompanied by a reduction in activity of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) that contributes to abnormal Ca(2+) homeostasis in sarco/endoplasmic reticulum (SR/ER). Recent findings suggest that skeletal muscle fatty acid synthase (FAS) modulates SERCA activity and muscle function via its effects on SR membrane phospholipids. In this study, we examined muscle's lipid metabolism in mdx mice, a mouse model for Duchenne muscular dystrophy (DMD). De novo lipogenesis was ~50% reduced in mdx muscles compared to wildtype (WT) muscles. Gene expressions of lipogenic and other ER lipid-modifying enzymes were found to be differentially expressed between wildtype (WT) and mdx muscles. A comprehensive examination of muscles' SR phospholipidome revealed elevated phosphatidylcholine (PC) and PC/phosphatidylethanolamine (PE) ratio in mdx compared to WT mice. Studies in primary myocytes suggested that defects in key lipogenic enzymes including FAS, stearoyl-CoA desaturase-1 (SCD1), and Lipin1 are likely contributing to reduced SERCA activity in mdx mice. Triple transgenic expression of FAS, SCD1, and Lipin1 (3TG) in mdx myocytes partly rescued SERCA activity, which coincided with an increase in SR PE that normalized PC/PE ratio. These findings implicate a defect in lipogenesis to be a contributing factor for SERCA dysfunction in muscular dystrophy. Restoration of muscle's lipogenic pathway appears to mitigate SERCA function through its effects on SR membrane composition.
authors.affiliation: Department of Kinesiology, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA; Department of Physiology, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Paran
authors.affiliation: Department of Kinesiology, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Zou
authors.affiliation: Department of Kinesiology, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Ferrara
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
authors.forename: Haowei
authors.initials: H
authors.lastname: Song
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.affiliation: Department of Kinesiology, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA; Department of Physiology, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA. Electronic address: funaik@ecu.edu.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Funai
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D050155:Lipogenesis; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism; D010713:Phosphatidylcholines / Q000096:biosynthesis* / Q000235:genetics; D010714:Phosphatidylethanolamines / Q000096:biosynthesis* / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C483858:phosphatidylethanolamine; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D054890:Fatty Acid Synthase, Type I; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Calcium; Lipogenesis; Membrane phospholipid; Muscular dystrophy; Sarcoplasmic reticulum