title: Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles.
abstract: AMP-activated protein kinase (AMPK) is a master regulator of metabolism. While muscle-specific AMPK β1β2 double-knockout (β1β2M-KO) mice display alterations in metabolic and mitochondrial capacity, their severe exercise intolerance suggested a secondary contributor to the observed phenotype. We find that tibialis anterior (TA), but not soleus, muscles of sedentary β1β2M-KO mice display a significant myopathy (decreased myofiber areas, increased split and necrotic myofibers, and increased centrally nucleated myofibers. A mitochondrial- and fiber-type-specific etiology to the myopathy was ruled out. However, β1β2M-KO TA muscles displayed significant (P<0.05) increases in platelet aggregation and apoptosis within myofibers and surrounding interstitium (P<0.05). These changes correlated with a 45% decrease in capillary density (P<0.05). We hypothesized that the β1β2M-KO myopathy in resting muscle resulted from impaired AMPK-nNOSμ signaling, causing increased platelet aggregation, impaired vasodilation, and, ultimately, ischemic injury. Consistent with this hypothesis, AMPK-specific phosphorylation (Ser1446) of nNOSμ was decreased in β1β2M-KO compared to wild-type (WT) mice. The AMPK-nNOSμ relationship was further demonstrated by administration of 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) to β1β2-MKO muscles and C2C12 myotubes. AICAR significantly increased nNOSμ phosphorylation and nitric oxide production (P<0.05) within minutes of administration in WT muscles and C2C12 myotubes but not in β1β2M-KO muscles. These findings highlight the importance of the AMPK-nNOSμ pathway in resting skeletal muscle.
authors: 2Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St. West, Hamilton, ON L8S4L8, Canada. hawke@mcmaster.ca.
authors: Melissa M
authors: MM
authors: Thomas
authors: David C
authors: DC
authors: Wang
authors: Donna M
authors: DM
authors: D'Souza
authors: Matthew P
authors: MP
authors: Krause
authors: Andrew S
authors: AS
authors: Layne
authors: David S
authors: DS
authors: Criswell
authors: Hayley M
authors: HM
authors: O'Neill
authors: Michael K
authors: MK
authors: Connor
authors: Judy E
authors: JE
authors: Anderson
authors: Bruce E
authors: BE
authors: Kemp
authors: Gregory R
authors: GR
authors: Steinberg
authors: Thomas J
authors: TJ
authors: Hawke
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000378:metabolism*; D002460:Cell Line; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D007511:Ischemia / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000473:pathology*; D009135:Muscular Diseases / Q000473:pathology*; D009336:Necrosis / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010766:Phosphorylation; D010974:Platelet Aggregation; D012265:Ribonucleotides / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D012265:Ribonucleotides; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; C569522:Prkab2 protein, mouse; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: NO signaling; necrosis; nitric oxide synthase