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

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Nutrient excess increases skeletal muscle oxidant production and mitochondrial fragmentation that may result in impaired mitochondrial function, a hallmark of skeletal muscle insulin resistance. This led us to explore whether an endogenous gas molecule, carbon monoxide (CO), which is thought to prevent weight gain and metabolic dysfunction in mice consuming high-fat diets, alters mitochondrial morphology and respiration in C2C12 myoblasts exposed to high glucose (15.6 mM) and high fat (250 µM BSA-palmitate) (HGHF). Also, skeletal muscle mitochondrial morphology, distribution, respiration, and energy expenditure were examined in obese resistant (OR) and obese prone (OP) rats that consumed a high-fat and high-sucrose diet for 10 wk with or without intermittent low-dose inhaled CO and/or exercise training. In cells exposed to HGHF, superoxide production, mitochondrial membrane potential (ΔΨm), mitochondrial fission regulatory protein dynamin-related protein 1 (Drp1) and mitochondrial fragmentation increased, while mitochondrial respiratory capacity was reduced. CO decreased HGHF-induced superoxide production, Drp1 protein levels and mitochondrial fragmentation, maintained ΔΨm, and increased mitochondrial respiratory capacity. In comparison with lean OR rats, OP rats had smaller skeletal muscle mitochondria that contained disorganized cristae, a normal mitochondrial distribution, but reduced citrate synthase protein expression, normal respiratory responses, and a lower energy expenditure. The combination of inhaled CO and exercise produced the greatest effect on mitochondrial morphology, increasing ADP-stimulated respiration in the presence of pyruvate, and preventing a decline in resting energy expenditure. These data support a therapeutic role for CO and exercise in preserving mitochondrial morphology and respiration during metabolic overload.





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Gasier, Heath G, Jacob Dohl, Hagir B Suliman, Claude A Piantadosi and Tianzheng Yu (2020). Skeletal muscle mitochondrial fragmentation and impaired bioenergetics from nutrient overload are prevented by carbon monoxide. American journal of physiology. Cell physiology, 319(4). pp. C746–C756. 10.1152/ajpcell.00016.2020 Retrieved from

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Heath Gasier

Associate Professor in Anesthesiology

I am a physiologist who joined Duke University in 2019 after retiring from military service. My research has focused on understanding how oxidant stress impacts cellular and systems physiology. Initially, I studied in humans how hyperbaric oxygen (HBO2) within the therapeutic range and high altitude influence nitric oxide production, antioxidant defenses, tissue oxygenation and muscle performance. This work sparked my interest in redox biology and led me to train under Dr. Claude A. Piantadosi at Duke University. Here, I began to study in mice and rats the impact of extreme HBO2 on the central nervous system (CNS). The objectives were to identify in rodents the origin and mechanisms of CNS oxygen toxicity, and test targeted pharmacological intervention strategies. It was during this time that I became interested in heme oxygenase 1 (HO-1). During my final military assignment, I continued to work on HBO2 and CNS oxygen toxicity related research (pharmacological intervention) and initiated new studies examining how HO-1 induction influences musculoskeletal health in diet-induced obesity. These studies led to follow-on work aimed at determining the mechanisms of HO-1 induction and mitochondrial dynamic regulation in an in vitro model of diet-induced obesity. In addition, I was involved in research aimed at understanding how antioxidants influence skeletal muscle mitochondrial dynamics in rodents and cells exposed heat stress and extreme high altitude.

Since returning to Duke University, I continue to conduct research focused on understanding how oxidant stress induced by HBO2 and obesity influences mitochondrial dynamic regulation in the brain, lung and skeletal muscle. I am now studying how sarcopenia and gender influence these responses. I am also involved (Co-I) in research testing the efficacy of a home-based high intensity interval training program in COVID-19 critical illness and early parenteral nutrition in abdominal trauma victims. In both of these studies, my efforts will be directed towards measuring inflammation and mitochondrial quality control responses to the interventions, which are linked to HO-1 activation.


Claude Anthony Piantadosi

Professor Emeritus of Medicine

Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species transmit biological signals involved in the maintenance of energy metabolism and mitochondrial health, but also contribute to pathogenesis and to the resolution of tissue injury.

Clinically, ALI and the related syndrome of multiple organ failure has a high mortality, which is related to the host inflammatory response, but is not well understood scientifically; thus, the laboratory is devoted to understanding these mechanisms in the context of the host response to relevant but well-controlled experimental manipulations including hyperoxia, bacterial infections, toxic drugs, and cytokine/chemokine signals. The approach relies on animal models, mainly transgenic and knockout mice, and cell models, especially lung and heart cells to evaluate and understand the physiology, pathology, and cell and molecular biology of the injury responses, to test independent and integrated mechanisms, and to devise interventions to prevent damage.

Apart from the lung, significant work is devoted to understanding damage to the heart, brain, liver, and kidney caused by these immune mechanisms, specifically emphasizing the role of mitochondria, key targets and sources of oxidative damage. This damage compromises their ability to support energy homeostasis and advanced cellular functions, and impacts on the important roles these organelles play in cell death by apoptosis and necrosis as well as in the resolution of cellular damage and inflammation.

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