title: ATGL-mediated triglyceride turnover and the regulation of mitochondrial capacity in skeletal muscle.
abstract: Emerging evidence indicates that skeletal muscle lipid droplets are an important control point for intracellular lipid homeostasis and that regulating fatty acid fluxes from lipid droplets might influence mitochondrial capacity. We used pharmacological blockers of the major triglyceride lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase, to show that a large proportion of the fatty acids that are transported into myotubes are trafficked through the intramyocellular triglyceride pool. We next tested whether increasing lipolysis from intramyocellular lipid droplets could activate transcriptional responses to enhance mitochondrial and fatty acid oxidative capacity. ATGL was overexpressed by adenoviral and adenoassociated viral infection in C2C12 myotubes and the tibialis anterior muscle of C57Bl/6 mice, respectively. ATGL overexpression in C2C12 myotubes increased lipolysis, which was associated with increased peroxisome proliferator-activated receptor (PPAR)-∂ activity, transcriptional upregulation of some PPAR∂ target genes, and enhanced mitochondrial capacity. The transcriptional responses were specific to ATGL actions and not a generalized increase in fatty acid flux in the myotubes. Marked ATGL overexpression (20-fold) induced modest molecular changes in the skeletal muscle of mice, but these effects were not sufficient to alter fatty acid oxidation. Together, these data demonstrate the importance of lipid droplets for myocellular fatty acid trafficking and the capacity to modulate mitochondrial capacity by enhancing lipid droplet lipolysis in vitro; however, this adaptive program is of minor importance when superimposing the normal metabolic stresses encountered in free-moving animals.
authors: Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria, Australia;
authors: Ruth C R
authors: RC
authors: Meex
authors: Discipline of Physiology, School of Medical Sciences & Bosch Institute, University of Sydney, New South Wales, Australia; Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, University of Sydney, Sydney, New South Wales, Australia;
authors: Andrew J
authors: AJ
authors: Hoy
authors: Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria, Australia;
authors: Rachael M
authors: RM
authors: Mason
authors: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Burwood, Victoria, Australia; and.
authors: Sheree D
authors: SD
authors: Martin
authors: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Burwood, Victoria, Australia; and.
authors: Sean L
authors: SL
authors: McGee
authors: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia.
authors: Clinton R
authors: CR
authors: Bruce
authors: Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria, Australia; matthew.watt@monash.edu.
authors: Matthew J
authors: MJ
authors: Watt
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D008049:Lipase / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics*; D008066:Lipolysis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D005227:Fatty Acids; D008049:Lipase; D047492:Peroxisome Proliferator-Activated Receptors; D014280:Triglycerides; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: adipose triglyceride lipase; fatty acid metabolism; lipolysis