Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans.

Given that the physiology of heme oxygenase-1 (HO-1) encompasses mitochondrial biogenesis, we tested the hypothesis that the HO-1 product, carbon monoxide (CO), activates mitochondrial biogenesis in skeletal muscle and enhances maximal oxygen uptake (Vo(2max)) in humans. In 10 healthy subjects, we biopsied the vastus lateralis and performed Vo(2max) tests followed by blinded randomization to air or CO breathing (1 h/day at 100 parts/million for 5 days), a contralateral muscle biopsy on day 5, and repeat Vo(2max) testing on day 8. Six independent subjects underwent CO breathing and two muscle biopsies without exercise testing. Molecular studies were performed by real-time RT-PCR, Western blot analysis, and immunochemistry. After Vo(2max) testing plus CO breathing, significant increases were found in mRNA levels for nuclear respiratory factor-1, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, mitochondrial transcription factor-A (Tfam), and DNA polymerase gamma (Polgamma) with no change in mitochondrial DNA (mtDNA) copy number or Vo(2max). Levels of myosin heavy chain I and nuclear-encoded HO-1, superoxide dismutase-2, citrate synthase, mitofusin-1 and -2, and mitochondrial-encoded cytochrome oxidase subunit-I (COX-I) and ATPase-6 proteins increased significantly. None of these responses were reproduced by Vo(2max) testing alone, whereas CO alone increased Tfam and Polgamma mRNA, and COX-I, ATPase-6, mitofusin-2, HO-1, and superoxide dismutase protein. These findings provide evidence linking the HO/CO response involved in mitochondrial biogenesis in rodents to skeletal muscle in humans through a set of responses involving regulation of the mtDNA transcriptosome and mitochondrial fusion proteins autonomously of changes in exercise capacity.

Effects of head and body cooling on hemodynamics during immersed prone exercise at 1 ATA.

Immersion pulmonary edema (IPE) is a condition with sudden onset in divers and swimmers suspected to be due to pulmonary arterial or venous hypertension induced by exercise in cold water, although it does occur even with adequate thermal protection. We tested the hypothesis that cold head immersion could facilitate IPE via a reflex rise in pulmonary vascular pressure due solely to cooling of the head. Ten volunteers were instrumented with ECG and radial and pulmonary artery catheters and studied at 1 atm absolute (ATA) during dry and immersed rest and exercise in thermoneutral (29-31 degrees C) and cold (18-20 degrees C) water. A head tent varied the temperature of the water surrounding the head independently of the trunk and limbs. Heart rate, Fick cardiac output (CO), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP), and central venous pressure (CVP) were measured. MPAP, PAWP, and CO were significantly higher in cold pool water (P < or = 0.004). Resting MPAP and PAWP values (means +/- SD) were 20 +/- 2.9/13 +/- 3.9 (cold body/cold head), 21 +/- 3.1/14 +/- 5.2 (cold/warm), 14 +/- 1.5/10 +/- 2.2 (warm/warm), and 15 +/- 1.6/10 +/- 2.6 mmHg (warm/cold). Exercise values were higher; cold body immersion augmented the rise in MPAP during exercise. MAP increased during immersion, especially in cold water (P < 0.0001). Except for a transient additive effect on MAP and MPAP during rapid head cooling, cold water on the head had no effect on vascular pressures. The results support a hemodynamic cause for IPE mediated in part by cooling of the trunk and extremities. This does not support the use of increased head insulation to prevent IPE.