title: Control of microvascular PO₂ kinetics following onset of muscle contractions: role for AMPK.
abstract: The microvascular partial pressure of oxygen (Pmv(o(2))) kinetics following the onset of exercise reflects the relationship between muscle O(2) delivery and uptake (Vo(2)). Although AMP-activated protein kinase (AMPK) is known as a regulator of mitochondria and nitric oxide metabolism, it is unclear whether the dynamic balance of O(2) delivery and Vo(2) at exercise onset is dependent on AMPK activation level. We used transgenic mice with muscle-specific AMPK dominant-negative (AMPK-DN) to investigate a role for skeletal muscle AMPK on Pmv(o(2)) kinetics following onset of muscle contractions. Phosphorescence quenching techniques were used to measure Pmv(o(2)) at rest and across the transition to twitch (1 Hz) and tetanic (100 Hz, 3-5 V, 4-ms pulse duration, stimulus duration of 100 ms every 1 s for 1 min) contractions in gastrocnemius muscles (each group n = 6) of AMPK-DN mice and wild-type littermates (WT) under isoflurane anesthesia with 100% inspired O(2) to avoid hypoxemia. Baseline Pmv(o(2)) before contractions was not different between groups (P > 0.05). Both muscle contraction conditions exhibited a delay followed by an exponential decrease in Pmv(o(2)). However, compared with WT, AMPK-DN demonstrated 1) prolongation of the time delay before Pmv(o(2)) began to decline (1 Hz: WT, 3.2 ± 0.5 s; AMPK-DN, 6.5 ± 0.4 s; 100 Hz: WT, 4.4 ± 1.0 s; AMPK-DN, 6.5 ± 1.4 s; P < 0.05), 2) a faster response time (i.e., time constant; 1 Hz: WT, 19.4 ± 3.9 s; AMPK-DN, 12.4 ± 2.6 s; 100 Hz: WT, 15.1 ± 2.2 s; AMPK-DN, 9.0 ± 1.7 s; P < 0.05). These findings are consistent with the presence of substantial mitochondrial and microvascular dysfunction in AMPK-DN mice, which likely slows O(2) consumption kinetics (i.e., oxidative phosphorylation response) and impairs the hyperemic response at the onset of contractions thereby sowing the seeds for exercise intolerance.
authors.affiliation: Dept. of Engineering Science, Bioscience and Technology Program, Univ. of Electro-Communications, Chofu,Tokyo, 1828585, Japan. kano@pc.uec.ac.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kano
authors.forename: David C
authors.initials: DC
authors.lastname: Poole
authors.forename: Mizuki
authors.initials: M
authors.lastname: Sudo
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hirachi
authors.forename: Shinji
authors.initials: S
authors.lastname: Miura
authors.forename: Osamu
authors.initials: O
authors.lastname: Ezaki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002196:Capillaries / Q000503:physiopathology*; D004558:Electric Stimulation; D004789:Enzyme Activation; D017079:Exercise Tolerance; D006940:Hyperemia / Q000201:enzymology / Q000503:physiopathology; D007700:Kinetics; D008163:Luminescent Measurements; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D008931:Mitochondria, Muscle / Q000201:enzymology; D009119:Muscle Contraction; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000201:enzymology* / Q000294:innervation; D009154:Mutation; D010100:Oxygen / Q000097:blood*; D010101:Oxygen Consumption; D010313:Partial Pressure
chemical_list: C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases; D010100:Oxygen