title: Up-regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor alpha (PPARalpha).
abstract: In insulin deficiency, increased lipid delivery and oxidation suppress skeletal-muscle glucose oxidation by inhibiting pyruvate dehydrogenase complex (PDC) activity via enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4, which phosphorylates (and inactivates) PDC. Signalling via peroxisome-proliferator-activated receptor alpha (PPARalpha) is an important component of the mechanism enhancing hepatic and renal PDK4 protein expression. Activation of PPARalpha in gastrocnemius, a predominantly fast glycolytic (FG) muscle, also increases PDK4 expression, an effect that, if extended to all muscles, would be predicted to drastically restrict whole-body glucose disposal. Paradoxically, chronic activation of PPARalpha by WY14,643 treatment improves glucose utilization by muscles of insulin-resistant high-fat-fed rats. In the resting state, oxidative skeletal muscles are quantitatively more important for glucose disposal than FG muscles. We evaluated the participation of PPARalpha in regulating PDK4 protein expression in slow oxidative (SO) skeletal muscle (soleus) and fast oxidative-glycolytic (FOG) skeletal muscle (anterior tibialis) containing a high proportion of oxidative fibres. In the fed state, acute (24 h) activation of PPARalpha by WY14,643 in vivo failed to modify PDK4 protein expression in soleus, but modestly enhanced PDK4 protein expression in anterior tibialis. Starvation enhanced PDK4 protein expression in both muscles, with the greater response in anterior tibialis. WY14,643 treatment in vivo during starvation did not further enhance upregulation of PDK4 protein expression in either muscle type. Enhanced PDK4 protein expression after starvation was retained in SO and FOG skeletal muscles of PPARalpha-deficient mice. Our data indicate that PDK4 protein expression in oxidative skeletal muscle is regulated by a lipid-dependent mechanism that is not obligatorily dependent on signalling via PPARalpha.
authors.affiliation: Department of Diabetes and Metabolic Medicine, Barts & the London, Queen Mary's School of Medicine and Dentistry, University of London, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Holness
authors.forename: Karen
authors.initials: K
authors.lastname: Bulmer
authors.forename: Geoffrey F
authors.initials: GF
authors.lastname: Gibbons
authors.forename: Mary C
authors.initials: MC
authors.lastname: Sugden
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005508:Food Deprivation; D015151:Immunoblotting; D008024:Ligands; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018656:Muscle Fibers, Fast-Twitch / Q000201:enzymology; D018482:Muscle, Skeletal / Q000201:enzymology*; D010100:Oxygen / Q000378:metabolism*; D020033:Protein Isoforms; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; C000631439:Pdk4 protein, mouse; C000631440:Pdk4 protein, rat; D020033:Protein Isoforms; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D010100:Oxygen