title: The effects of chronic muscle use and disuse on cardiolipin metabolism.
abstract: Cardiolipin (CL) is a phospholipid that maintains the integrity of mitochondrial membranes. We previously demonstrated that CL content increases with chronic muscle use, and decreases with denervation-induced disuse. To investigate the underlying mechanisms, we measured the mRNA expression of 1) CL synthesis enzymes cardiolipin synthase (CLS) and CTP:PA-cytidylyltransferase-1 (CDS-1); 2) remodeling enzymes tafazzin and acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1); and 3) outer membrane CL enzymes, mitochondrial phospholipase D and phospholipid scramblase 3 (Plscr3), during chronic contractile activity (CCA)-induced mitochondrial biogenesis and denervation. With CCA, CDS-1 expression increased by 128%, parelleling CL levels. Surprisingly, denervation also led to large increases in CDS-1 and CLS, despite a decrease in mitochondria, possibly due to a compensatory mechanism to restore lost CL. ALCAT1 decreased by 32% with CCA, but increased by 290% following denervation, indicating that both CCA and denervation alter CL remodeling. CCA and denervation also elicited 60-90% increases in Plscr3, likely to facilitate CL movement to the outer membrane. The expression of these genes was not affected by aging, but changes due to CCA and denervation were attenuated compared with young animals. The absence of PPARγ coactivator-1α in knockout animals led to a decrease in CDS-1 and an increase in ALCAT1 mRNA levels, implicating PGC-1α in regulating both CL synthesis and remodeling. These data suggest that chronic muscle use and disuse modify the expression of mRNAs encoding CL metabolism enzymes. Our data also illustrate, for the first time, that PPARγ coactivator-1α regulates the CL metabolism pathway in muscle.
authors.affiliation: School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Ostojic
authors.forename: Michael F N
authors.initials: MF
authors.lastname: O'Leary
authors.forename: Kaustabh
authors.initials: K
authors.lastname: Singh
authors.forename: Keir J
authors.initials: KJ
authors.lastname: Menzies
authors.forename: Anna
authors.initials: A
authors.lastname: Vainshtein
authors.forename: David A
authors.initials: DA
authors.lastname: Hood
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D019916:Choline-Phosphate Cytidylyltransferase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009119:Muscle Contraction; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism* / Q000503:physiopathology; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D008565:Membrane Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D049294:Phospholipid Transfer Proteins; C493428:Plscr3 protein, mouse; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D000217:Acyltransferases; C544439:Tafazzin protein, rat; C525544:lysocardiolipin acyltransferase, mouse; D019916:Choline-Phosphate Cytidylyltransferase; D017855:Transferases (Other Substituted Phosphate Groups); C100091:cardiolipin synthetase; D010739:Phospholipase D