title: PPARγ coactivator-1α contributes to exercise-induced regulation of intramuscular lipid droplet programming in mice and humans.
abstract: Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities. Herein, we show that acute exercise elicits robust upregulation of a broad program of genes involved in regulating LD assembly, morphology, localization, and mobilization. Prominent among these was perilipin-5, a scaffolding protein that affects the spatial and metabolic interactions between LD and their surrounding mitochondrial reticulum. Studies in transgenic mice and primary human skeletal myocytes established a key role for the exercise-responsive transcriptional coactivator PGC-1α in coordinating intramuscular LD programming with mitochondrial remodeling. Moreover, translational studies comparing physically active versus inactive humans identified a remarkably strong association between expression of intramuscular LD genes and enhanced insulin action in exercise-trained subjects. These results reveal an intimate molecular connection between intramuscular LD biology and mitochondrial metabolism that could prove relevant to the etiology and treatment of insulin resistance and other disorders of lipid imbalance.
authors.affiliation: Sarah W. Stedman Nutrition & Metabolism Center, Duke University, Durham, NC, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Sparks
authors.forename: J P
authors.initials: JP
authors.lastname: Kovalik
authors.forename: Merrie
authors.initials: M
authors.lastname: Mosedale
authors.forename: Ramamani
authors.initials: R
authors.lastname: Arumugam
authors.forename: Karen L
authors.initials: KL
authors.lastname: DeBalsi
authors.forename: Karen
authors.initials: K
authors.lastname: Everingham
authors.forename: Leigh
authors.initials: L
authors.lastname: Thorne
authors.forename: Esther
authors.initials: E
authors.lastname: Phielix
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Meex
authors.forename: C Lawrence
authors.initials: CL
authors.lastname: Kien
authors.forename: Matthijs K C
authors.initials: MK
authors.lastname: Hesselink
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
mesh_terms: D000818:Animals; D015444:Exercise; D005260:Female; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D015388:Organelles / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides