Loss of ARNT Limits Improvement in Physiological Performance Following Aerobic Exercise in Aging

Hypoxia signaling is essential for angiogenesis and metabolic regulation during exercise. Our previous study has demonstrated an age-related loss of ARNT resulting in limited muscle regeneration. To explore the role of hypoxia signaling in physiological performance in relation to aging, we generated a mouse model with skeletal muscle-specific knockout of ARNT (ARNT mKO). ARNT mKO and ARNT WT mice were subjected to a sedentary activity or treadmill running exercise regime at an increasing speed of 8-12 m/min for 40 minutes, three times weekly over the course of 8 weeks. ARNT levels was 3-fold lower in old mice compared to young. The exercised WT mice exhibited 52% greater increase over the sedentary group in exercise endurance as measured by the maximum running distance (490.92±154.28 vs 237.76±135.19m, p＜0.01). In contrast, ARNT mKO mice did not benefit from exercise (231.85±198.61 vs 167.27±136.56m, p=0.41). The maximum running speed was severely restricted in the trained ARNT mKO mice versus WT (16±1.63 m/min vs 26.67±2.45 m/min, p＜0.001). Cross-sectional area of myofibers increased significantly following exercise in WT mice (2270 vs 2960 □m2, p=0,015) indicating muscle hypertrophic response, while no change was observed in the ARNT mKO group (2101 vs 2378□m2, p=0,21). Further, exercise increased femoral artery blood flow by 41% in ARNT WT mice, but not in ARNT mKO mice (898.96±52.33 vs 802.86±48.43, p=0.20). These data suggest that ARNT is essential for physiological response to exercise

Whole body passive heating versus dynamic lower body exercise: A comparison of peripheral hemodynamic profiles

Passive heating has emerged as a therapeutic intervention for the treatment and prevention of cardiovascular disease. Like exercise, heating increases peripheral artery blood flow and shear rate which is thought to be a primary mechanism underpinning endothelium mediated vascular adaptation. However, few studies have compared the increase in arterial blood flow and shear rate between dynamic exercise and passive heating. In a fixed crossover design study, 15 moderately trained healthy participants (25.6 ± 3.4 years) (5 female) underwent 30 minutes of whole body passive heating (42 °C bath), followed on a separate day by 30 minutes of semi-recumbent stepping exercise performed at two workloads corresponding to the increase in cardiac output (Qc) (Δ3.72 l∙min-1) and heart rate (HR) (Δ38 bpm) recorded at the end of passive heating. Results: At the same Qc (Δ3.72 l∙min-1 vs 3.78 l∙min-1), femoral artery blood flow (1599 ml/min vs 1947 ml/min) (p=0.596) and shear rate (162 s -1 vs 192 s-1) (p=0.471) measured by ultrasonography were similar between passive heating and stepping exercise. However, for the same HR matched intensity, femoral blood flow (1599 ml·min-1 vs 2588 ml·min-1) and shear rate (161s-1 vs 271s-1) were significantly greater during exercise, compared with heating (both P=<0.001). The results indicate that, for moderately trained individuals, passive heating increases common femoral artery blood flow and shear rate similar to low intensity continuous dynamic exercise (29% VO2max), however exercise performed at a higher intensity (53% VO2max) results in significantly larger shear rates towards the active skeletal muscle.

Metformin improves vascular and metabolic insulin action in insulin-resistant muscle

Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow, and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin-resistant rats. Sprague–Dawley rats were fed a normal (ND) or high-fat (HFD) diet for 4 weeks. A separate HFD group was given metformin in drinking water (HFD + MF, 150 mg/kg/day) during the final 2 weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-h euglycaemic–hyperinsulinaemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-AKT and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole-body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-AKT phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and free fatty acid concentrations and lowered body weight and adiposity. During euglycaemic-hyperinsulinaemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-AKT phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that 2-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin-resistant rats.

Diving and exercise: The interaction of trigeminal receptors and muscle metaboreceptors on muscle sympathetic nerve activity in humans

Swimming involves muscular activity and submersion, creating a conflict of autonomic reflexes elicited by the trigeminal receptors and skeletal muscle afferents. We sought to determine the autonomic cardiovascular responses to separate and concurrent stimulation of the trigeminal cutaneous receptors and metabolically sensitive skeletal muscle afferents (muscle metaboreflex). In eight healthy men (30 ± 2 yr) muscle sympathetic nerve activity (MSNA; microneurography), mean arterial pressure (MAP; Finometer), femoral artery blood flow (duplex Doppler ultrasonography), and femoral vascular conductance (femoral artery blood flow/MAP) were assessed during the following three experimental conditions: 1) facial cooling (trigeminal nerve stimulation), 2) postexercise ischemia (PEI; muscle metaboreflex activation) following isometric handgrip, and 3) trigeminal nerve stimulation with concurrent PEI. Trigeminal nerve stimulation produced significant increases in MSNA total activity (Δ347 ± 167%) and MAP (Δ21 ± 5%) and a reduction in femoral artery vascular conductance (Δ−17 ± 9%). PEI also evoked significant increases in MSNA total activity (Δ234 ± 83%) and MAP (Δ36 ± 4%) and a slight nonsignificant reduction in femoral artery vascular conductance (Δ−9 ± 12%). Trigeminal nerve stimulation with concurrent PEI evoked changes in MSNA total activity (Δ341 ± 96%), MAP (Δ39 ± 4%), and femoral artery vascular conductance (Δ−20 ± 9%) that were similar to those evoked by either separate trigeminal nerve stimulation or separate PEI. Thus, excitatory inputs from the trigeminal nerve and metabolically sensitive skeletal muscle afferents do not summate algebraically in eliciting a MSNA and cardiovascular response but rather exhibit synaptic occlusion, suggesting a high degree of convergent inputs on output neurons.

Spectral analysis of femoral artery blood flow waveforms of conscious domestic cats

The qualitative and quantitative aspects of femoral artery blood flow waveform spectra were evaluated in 15 male and 15 female Persian and mixed breed domestic cats ( Felis catus), which were healthy and not sedated, using duplex Doppler ultrasonography (DDU). Spectral Doppler demonstrated a biphasic characteristic in 16 (53.34%) of the animals evaluated, and a triphasic characteristic in the 14 (46.66%) remaining animals. The systolic blood pressure and heart rate values were within the normal range for the species. The quantitative parameters evaluated, based on the spectral Doppler, were as follows: systolic velocity peak (SVP), recent diastolic velocity peak (RDVP), end diastolic velocity peak (EDVP), mean velocity (MV), integral velocity time (ITV), artery diameter (AD), femoral flow volume (FFV), pulsatility index (PI), resistive index (RI), systolic peak acceleration time (AT) and deceleration time (DT). The respective mean values were: 36.41 ± 7.33 cm/s, 4.69 ± 0.90 cm/s, 10.74 ± 2.74 cm/s, 23.06 ± 4.86 cm/s, 3.91 ± 1.05 cm, 0.17 ± 0.04 cm, 0.11 ± 0.08 cm3, 3.85 ± 0.19, 1.40 ± 0.20, 39.84 ± 7.38 ms, and 114.0 ± 22.15 ms. No significant differences were found between males and females. The analyses carried out on the femoral artery flow spectrum obtained by DDU showed that it is easy to use and highly tolerated in non-sedated, healthy cats. It appears that DDU may be a useful diagnostic technique, but further studies are needed to evaluate how it compares with invasive telemetric methodology or high-definition oscillometric waveform analytic techniques.

Local NOS inhibition impairs vascular and metabolic actions of insulin in rat hindleg muscle in vivo

Insulin stimulates microvascular recruitment in skeletal muscle, and this vascular action augments muscle glucose disposal by ∼40%. The aim of the current study was to determine the contribution of local nitric oxide synthase (NOS) to the vascular actions of insulin in muscle. Hooded Wistar rats were infused with the NOS inhibitor Nω-nitro-l-arginine methylester (l-NAME, 10 μM) retrogradely via the epigastric artery in one leg during a systemic hyperinsulinemic-euglycemic clamp (3 mU·min−1·kg−1 × 60 min) or saline infusion. Femoral artery blood flow, microvascular blood flow (assessed from 1-methylxanthine metabolism), and muscle glucose uptake (2-deoxyglucose uptake) were measured in both legs. Local l-NAME infusion did not have any systemic actions on blood pressure or heart rate. Local l-NAME blocked insulin-stimulated changes in femoral artery blood flow (84%, P < 0.05) and microvascular recruitment (98%, P < 0.05), and partially blocked insulin-mediated glucose uptake in muscle (reduced by 34%, P < 0.05). l-NAME alone did not have any metabolic effects in the hindleg. We conclude that insulin-mediated microvascular recruitment is dependent on local activation of NOS in muscle and that this action is important for insulin's metabolic actions.