Skeletal muscle mitochondrial fragmentation and impaired bioenergetics from nutrient overload are prevented by carbon monoxide

The prevalence of obesity is increasing in populations worldwide. Obesity is often part of the metabolic syndrome, a condition which includes insulin resistance, dyslipidemia, and hypertension. Metabolic syndrome increases the risk for development of cardiovascular diseases such as coronary artery disease and stroke.

The activation of stress response pathways in mitochondria can lead to changes in morphology, clearance (mitophagy) and generation of new mitochondria (biogenesis), tightly coupled processes that are linked to function. There is evidence of mitochondrial dysfunction in obese and insulin-resistant individuals, and in patients with type 2 diabetes mellitus.

Carbon monoxide (CO) is a colorless and odorless gas produced by combustion of carbon compounds such as those found in fossil fuels used in internal combustion engines. CO can be toxic when inhaled acutely at concentrations > 500 parts per million (ppm) in rodents and 200 ppm in humans. CO alters oxygen transport in red blood cells resulting in hypoxia. CO is also produced endogenously in the body where it serves as a gaseous signaling molecule. CO is primarily produced via catabolism of heme by heme oxygenase (HO) enzymes. It has been explored as an experimental strategy to reduce obesity and prevent adipocyte mitochondrial adaptations in mice consuming high-fat diets. While CO is considered to afford protection against diet-induced obesity in rodents, it remains unknown what effects CO has on skeletal muscle mitochondria when nutrient supply exceeds demand.

In a new study by Dr. Heath Gasier and colleagues from Duke University School of Medicine and the Uniformed Services University of the Health Sciences, they investigated the role of CO on mitochondrial morphology and respiration in C2C12 mouse primary myoblasts exposed to high-glucose and high-fat (HGHF). They also examined the anti-obesity potential of low-dose inhaled CO (250 ppm for 1 h) with and without aerobic exercise in obese prone rats by measuring skeletal muscle mitochondrial morphology and respiration, and total energy expenditure. The original research article is published in the American Journal of Physiology-Cell Physiology.

The research team found that in cells exposed to HGHF, 20 µM of carbon monoxide-releasing molecule 3 (CORM-3) reduced cellular and mitochondrial superoxide production, improved mitochondrial morphology and preserved mass. In addition, CORM-3 increased basal respiration, ATP turnover and maximal uncoupled respiration, and preserved mitochondrial membrane potential (Δψm) in HGHF exposed cells. The introduction of intermittent low-dose inhaled CO provided no protection against the effects of diet-induced obesity on mitochondrial morphology. However, when it was combined with moderate aerobic exercise training, CO caused further improvements in mitochondrial morphology (compared with exercise alone), increased respiration in permeabilized muscle fibers stimulated by ADP in the presence of pyruvate, and increased total energy expenditure.

In conclusion, through this study, Dr. Heath Gasier and his colleagues have demonstrated that mitochondrial fragmentation and superoxide production induced by nutrient excess is reduced by CO delivered by CORM-3 with concomitant increase in respiratory capacity. They also showed that the combination of intermittent CO inhalation and moderate aerobic exercise prevented the usual effect of chronic nutrient stress on skeletal muscle mitochondrial morphology and resting energy expenditure. These findings support the notion that carbon monoxide and exercise have a therapeutic role in preserving the morphology and respiration of the mitochondria during periods of overfeeding. Further studies are required to identify the specific mechanisms by which chronic carbon monoxide treatment mediates these effects in obesity, and the appropriate dosing strategy with and without exercise.