Increased SOD2 in the diaphragm contributes to exercise-induced protection against ventilator-induced diaphragm dysfunction

Abstract

Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, prolonged MV results in rapid diaphragmatic atrophy and contractile dysfunction, collectively termed ventilator-induced diaphragm dysfunction (VIDD). Recent evidence reveals that endurance exercise training, performed prior to MV, protects the diaphragm against VIDD. While the mechanism(s) responsible for this exercise-induced protection against VIDD remain unknown, increased diaphragm antioxidant expression may be required. To investigate the role that increased antioxidants play in this protection, we tested the hypothesis that elevated levels of the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) is required to achieve exercise-induced protection against VIDD. Cause and effect was investigated in two ways. First, we prevented the exercise-induced increase in diaphragmatic SOD2 via delivery of an antisense oligonucleotide targeted against SOD2 post-exercise. Second, using transgene overexpression of SOD2, we determined the effects of increased SOD2 in the diaphragm independent of exercise training. Results from these experiments revealed that prevention of the exercise-induced increases in diaphragmatic SOD2 results in a loss of exercise-mediated protection against MV-induced diaphragm atrophy and a partial loss of protection against MV-induced diaphragmatic contractile dysfunction. In contrast, transgenic overexpression of SOD2 in the diaphragm, independent of exercise, did not protect against MV-induced diaphragmatic atrophy and provided only partial protection against MV-induced diaphragmatic contractile dysfunction. Collectively, these results demonstrate that increased diaphragmatic levels of SOD2 are essential to achieve the full benefit of exercise-induced protection against VIDD.

Chronic heart failure with diabetes mellitus is characterized by a severe skeletal muscle pathology

“…Mitochondrial ROS production was substantially elevated and proportionally greater at complex I in patients with D‐HF compared with other groups, while the gene expression of the mitochondrial antioxidant SOD2 was lower which may have compromised ROS clearance. Regarding the latter, recent data have shown levels of SOD2 are able to modulate mitochondrial ROS and dysfunction alongside atrophy in an animal model of mechanical ventilation . Taken together, the current data indicate a shift towards a pro‐oxidant state in D‐HF consistent with the observation that treatment with antioxidant therapies such as mitochondrial‐specific drugs or whole‐body exercise training can ameliorate oxidative stress in skeletal muscle and improve mitochondrial function, insulin sensitivity, and exercise capacity in CHF and DM .…”

RETRACTED: Opa1 Reduces Hypoxia-Induced Cardiomyocyte Death by Improving Mitochondrial Quality Control

“…Changes in sarcomere length during shortening and relengthening were captured and analyzed using SoftEdge TM software (IonOptix, Westwood, MA, United States). To evaluate Ca 2+ transients, cardiomyocytes were loaded with 0.5 µmol/L Fura2-AM (Life Technologies, Carlsbad, CA, United States), a Ca 2+ -sensitive indicator, for 10 min at 37 • C. IonOptix was used to record fluorescence emission and to simultaneously perform contractility measurements (Morton et al, 2019).…”

Tempol improves redox status in mdx dystrophic diaphragm muscle

“…27 Recently, it has been shown that increased SOD2 in rat diaphragm contributes to the prevention of contractile dysfunction and consequent loss of strength, as well as preventing proteolysis, suggesting that SOD2 plays a role in MuRF1 and Atrogin-1 mRNA. 28 In addition, SOD2 overexpression in the diaphragm provides partial protection against mitochondrial uncoupling, proving to be capable of protecting against mitochondrial dysfunction. 28 Furthermore, it has been shown to restore diaphragm capacity in mdx mice after tempol supplementation.…”

“…28 In addition, SOD2 overexpression in the diaphragm provides partial protection against mitochondrial uncoupling, proving to be capable of protecting against mitochondrial dysfunction. 28 Furthermore, it has been shown to restore diaphragm capacity in mdx mice after tempol supplementation. 11 This finding was associated with increased citrate synthase and lactate dehydrogenase enzyme activity levels compared to wild-type mice.…”