The beneficial effects of low-dose carbon monoxide and moderate intensity endurance exercise on metabolic and skeletal properties
Carbon monoxide (CO) is released with Fe2+upon heme degradation to biliverdin, a reaction catalyzed by heme oxygenase. CO is a metabolic gas with known beneficial metabolic properties, most notably asa potent stimulator of mitochondrial biogenesis. Moreover, induction of hemeoxygenase-1 increases differentiation of bone-marrow-derived mesenchymal stemcells into osteoblasts. Emerging evidence suggests that initial increases inbone mineral density observed in obesity are subsequently followed by reductionsin bone resorption and formation, resulting in reduced bone quality and enhancedsusceptibility to fracture. Therefore, we hypothesized that low-dose CO, with and without moderate intensity exercise, would protect bone from the negative effects of obesity. Obese-Prone (OP) and obese-resistant (OR) rats were used toexamine this hypothesis. For 10 weeks, OP rats were fed a high fat, high sucrose diet (42% energy from fat) and OR rats consumed a low fat, low sucrose diet (13% energy from fat). OP rats were divided into the following groups: sedentary (OP, n = 14), sedentary carbon monoxide(OP-CO, n = 10), exercise (OP-EX, n = 11) and CO+EX (OP-COEX, n = 6); OR (n = 9) rats served as lean, sedentary controls. The dosage of CO was 250 ppm for 1 hour administered in 5 doses pre-study, and biweekly during the 10 week study. Exercising rats were habituated to the treadmill over 2 weeks prior to undergoing 10 weeks of involuntary exercise training, 3 hours/week. Treadmill grade was maintained at 10%, and velocity was progressively increased from 20 m/min (week 1) to 25 m/min. Measurements included body mass, whole-body resting VO2, plasma insulin, leptin, microstructural properties of distal and mid-shaft femur, and femur mechanical testing. Statistical analysis was conducted using a one-way ANOVA with a Bonferroni correction. OP rats gained 155% more weight, displayed a 31% decrease in whole-body resting VO2, and exhibited a 300% and 206% increase in plasma insulin and leptin, respectively, compared to OR rats. While exercising OP rats attenuated weight gain and reduced plasma insulin and leptin levels, only the combination of CO and exercise resulted in a weight gain similar to that observed in OR rats, and increased their whole-body resting VO2 38% over OP rats. OP rats hada 16% higher cortical bone area (B.Ar), 48% higher polar moment of inertia and 23% higher stiffness compared to OR animals. Combined CO and exercise normalizedB.Ar to levels of OR rats and exhibited a 36% increase in distal femurtrabecular number compared to OP and OR rats. These preliminary data highlightthe potential benefits of moderate intensity exercise combined with CO toameliorate obesity driven metabolic dysfunction and associated changes to bone.