To unravel the mechanisms by which maximal oxygen uptake (VO2 max) is reduced with severe acute hypoxia in humans, nine Danish lowlanders performed incremental cycle ergometer exercise to exhaustion, while breathing room air (normoxia) or 10.5% O2 in N2 (hypoxia, approximately 5,300 m above sea level). With hypoxia, exercise PaO2 dropped to 31-34 mmHg and arterial O2 content (CaO2) was reduced by 35% (P < 0.001). Forty-one percent of the reduction in CaO2 was explained by the lower inspired O2 pressure (PiO2) in hypoxia, whereas the rest was due to the impairment of the pulmonary gas exchange, as reflected by the higher alveolar-arterial O2 difference in hypoxia (P < 0.05). Hypoxia caused a 47% decrease in VO2 max (a greater fall than accountable by reduced CaO2). Peak cardiac output decreased by 17% (P < 0.01), due to equal reductions in both peak heart rate and stroke VOlume (P < 0.05). Peak leg blood flow was also lower (by 22%, P < 0.01). Consequently, systemic and leg O2 delivery were reduced by 43 and 47%, respectively, with hypoxia (P < 0.001) correlating closely with VO2 max (r = 0.98, P < 0.001). Therefore, three main mechanisms account for the reduction of VO2 max in severe acute hypoxia: 1) reduction of PiO2, 2) impairment of pulmonary gas exchange, and 3) reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in VO2 max.

SUMMARY Brown adipose tissue (BAT) is an energy-dispensing thermogenic tissue that plays an important role in balancing energy metabolism. Lineage-tracing experiments indicate that brown adipocytes are derived from myogenic progenitors during embryonic development. However, adult skeletal muscle stem cells (satellite cells) have long been considered uniformly determined toward the myogenic lineage. Here, we report that adult satellite cells give rise to brown adipocytes and that microRNA-133 regulates the choice between myogenic and brown adipose determination by targeting the 3′UTR of Prdm16. Antagonism of microRNA-133 during muscle regeneration increases uncoupled respiration, glucose uptake, and thermogenesis in local treated muscle and augments whole-body energy expenditure, improves glucose tolerance, and impedes the development of diet-induced obesity. Finally, we demonstrate that miR-133 levels are downregulated in mice exposed to cold, resulting in de novo generation of satellite cell-derived brown adipocytes. Therefore, microRNA-133 represents an important therapeutic target for the treatment of obesity.

Background-In chronic hypoxia, both heart rate (HR) and cardiac output (Q) are reduced during exercise. The role of parasympathetic neural activity in lowering HR is unresolved, and its influence on Q and oxygen transport at high altitude has never been studied. Methods and Results-HR, Q, oxygen uptake, mean arterial pressure, and leg blood flow were determined at rest and during cycle exercise with and without vagal blockade with glycopyrrolate in 7 healthy lowlanders after 9 weeks' residence at Ն5260 m (ALT). At ALT, glycopyrrolate increased resting HR by 80 bpm (73Ϯ4 to 153Ϯ4 bpm) compared with 53 bpm (61Ϯ3 to 114Ϯ6 bpm) at sea level (SL). During exercise at ALT, glycopyrrolate increased HR by Ϸ40 bpm both at submaximal (127Ϯ4 to 170Ϯ3 bpm; 118 W) and maximal (141Ϯ6 to 180Ϯ2 bpm) exercise, whereas at SL, the increase was only by 16 bpm (137Ϯ6 to 153Ϯ4 bpm) at 118 W, with no effect at maximal exercise (181Ϯ2 bpm). Despite restoration of maximal HR to SL values, glycopyrrolate had no influence on Q, which was reduced at ALT. Breathing FIO 2 ϭ0.55 at peak exercise restored Q and power output to SL values. Conclusions-Enhanced parasympathetic neural activity accounts for the lowering of HR during exercise at ALT without influencing Q. The abrupt restoration of peak exercise Q in chronic hypoxia to maximal SL values when arterial PO 2 and SO 2 are similarly increased suggests hypoxia-mediated attenuation of Q. Key Words: heart rate Ⅲ cardiac output Ⅲ hypoxia Ⅲ nervous system, autonomic Ⅲ exercise A cclimatization to high altitude induces alterations in autonomic neural control of the cardiovascular system, exemplified by a marked reduction in maximal heart rate (HR). [1][2][3][4] Christensen and Forbes 1 first described the reduction in peak exercise HR at high altitude in 1937, yet the mechanism underlying this response has remained elusive for Ͼ60 years. Adaptations in both parasympathetic and sympathetic neural tone have been implicated in the relative bradycardia response to exercise in chronic hypoxia. A progressive influence of parasympathetic activity on HR occurs with duration of altitude exposure either via a central effect of hypoxia, 4,5 by greater influence at the cardiac receptor level, 6 -8 or by cholinergic antagonism. 9 It has not been clearly shown whether enhanced vagal tone actually causes the lower HR, ie, by a direct adaptation to hypoxia, or whether a greater vagal influence is exhibited due to a lowering of HR by another mechanism, eg, lower sympathetic activation, reduced cardiac sensitivity to adrenergic stimulation, or modulation by other (eg, adenosinergic) receptors. 8,10,11 Furthermore, studies on parasympathetic neural control of HR in hypoxia have yielded discrepant findings. 4,12,13 The functional significance of vagal control of HR at altitude for systemic oxygen transport and hemodynamic responses has also never been studied. In this regard, a reduction in maximal cardiac output (Q) and oxygen delivery during exercise has also been documented with altitude acclimatization, 3,14 -...