title: Effect of LKB1 deficiency on mitochondrial content, fibre type and muscle performance in the mouse diaphragm.
abstract: OBJECTIVE
  The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signalling pathway is a major regulator of skeletal muscle metabolic processes. During exercise, LKB1-mediated phosphorylation of AMPK leads to its activation, promoting mitochondrial biogenesis and glucose transport, among other effects. The roles of LKB1 and AMPK have not been fully characterized in the diaphragm.
  
  
  METHODS
  Two methods of AMPK activation were used to characterize LKB1/AMPK signalling in diaphragms from muscle-specific LKB1 knockout (KO) and littermate control mice: (1) acute injection of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and (2) 5-min direct electrical stimulation of the diaphragm. Diaphragms were excised 60 min post-AICAR injection and immediately after electrical stimulation.
  
  
  RESULTS
  AMPK phosphorylation increased with AICAR and electrical stimulation in control but not KO mice. Acetyl CoA carboxylase phosphorylation increased with AICAR in control but not KO mice, but increased in both genotypes with electrical stimulation. While the majority of mitochondrial protein levels were lower in KO diaphragms, uncoupling protein 3, complex I and cytochrome oxidase IV protein levels were not different between genotypes. KO diaphragms have a lower percentage of IIx fibres and an elevated percentage of IIb fibres when compared with control diaphragms. While in vitro peak force generation was similar between genotypes, KO diaphragms fatigued more quickly and had an impaired ability to recover.
  
  
  CONCLUSIONS
  LKB1 regulates AMPK phosphorylation, mitochondrial protein expression, fibre type distribution, as well as recovery of the diaphragm from fatigue.
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Brown
authors.forename: C R
authors.initials: CR
authors.lastname: Hancock
authors.forename: A D
authors.initials: AD
authors.lastname: Mongillo
authors.forename: J
authors.initials: J
authors.lastname: Benjamin Barton
authors.forename: R A
authors.initials: RA
authors.lastname: DiGiovanni
authors.forename: A C
authors.initials: AC
authors.lastname: Parcell
authors.forename: W W
authors.initials: WW
authors.lastname: Winder
authors.forename: D M
authors.initials: DM
authors.lastname: Thomson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003964:Diaphragm / Q000033:anatomy & histology* / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D004789:Enzyme Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide