The microvascular partial pressure of oxygen (PmvO2) kinetics following the onset of exercise reflects the relationship between muscle O2 delivery and uptake (VO2). 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 O2 delivery and VO2 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 PmvO2 kinetics following onset of muscle contraction. Phosphorescence quenching techniques were used to measure PmvO2 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 O2 to avoid hypoxemia. Baseline PmvO2 before contractions was not different between groups (P > 0.05). Both muscle contraction conditions exhibited a delay followed by an exponential decrease in PmvO2. However, compared with WT, AMPK-DN demonstrated (1) prolongation of the time delay before PmvO2 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 O2 consumption kinetics (i.e. oxidative phosphorylation response) and impairs the hyperemic response at the onset of contractions thereby sowing the seeds for exercise intolerance.
- adenosine 5'-monophosphate-activated protein kinase
- phosphorescence quenching
- oxygen exchange
- transgenic mouse model
- Copyright © 2011, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology