Hyperoxia impacts heme oxygenase 1 and mitochondrial quality control in a rodent model of sarcopenic obesity
Authors: Gasier Heath 
Published: May 2024

Critically ill sarcopenic obese (SO) patients may be at higher risk for other complications and require mechanical ventilation, extending length of stay and recovery time. It may be because in sarcopenia and obesity, oxidants, inflammation and mitochondrial fragmentation increase, impacting respiration. Heme oxygenase 1 (HO-1) is an enzyme critical for cellular antioxidant and anti-inflammatory defenses, and in the regulation of mitochondrial quality control (MQC). Whether HO-1 signaling is impaired in SO during heightened oxidant stress remains unknown, the hypothesis of this research. Young (7-week-old) and old (72-week-old) C57BL/6J mice consumed high-fat (58%) or control (11% fat) diets for 16-weeks. Mean body weight (g), glucose AUC and strength (N) (±SD) measured after dietary interventions were as follows: young lean (33±2, 540±220, 1.9±0.3), young obese (53±3, 710±116, 1.8±0.4), old lean (38±4, 597±148, 1.5±0.3), and old obese (57±10, 654±119, 1.4±0.2). To induce oxidant stress, mice were exposed to 100% oxygen for 48 h. Lower hindlimb skeletal muscle was harvested 16 h later. Oxidant stress and inflammation were determined by measuring superoxide (DHE), DNA oxidation (8-OHdG), mitochondrial DNA lesions and cytochrome b mRNA, and IL-10, IL-1β and TNF-α protein expression. MQC was assessed by measuring regulators of mitochondrial fission (DRP1) and fusion (MFN1 and 2), mitophagy (PINK1, Parkin and LC3-II), and mitochondrial biogenesis (NFE2L2, PGC-1α, NRF1 and 2, and TFAM). The mitochondrial membrane potential was measured using TMRM. In contrast to air controls where HO-1 protein expression was increased by aging and obesity, hyperoxia caused substantial reductions in both HO-1 protein and mRNA within old and obese mice. The greatest reductions were found in SO (25% of young lean). The changes in HO-1 were accompanied by the following responses to hyperoxia: One, superoxide and DNA oxidation increased in old and obese mice by as much as 200%, leading to elevated mitochondrial DNA lesions and reduced cytochrome b. Two, IL-1β and TNF-α increased in aged mice by 41-129% over young mice, whereas IL-10 was lower (-33%) only in SO. Three, regulators of mitochondrial fission and fusion and mitophagy were reduced by aging and obesity, being lower in sarcopenia which may explain why mitochondrial LC3-II was only reduced in these mice. Fourth, modulators of mitochondrial biogenesis were decreased by aging and obesity, suggesting a reduced mitochondrial population. Lastly, the increased mitochondrial membrane potential measured in young obese (78%) and old lean (58%) mice was not observed in SO, indicating reduced mitochondrial activity. In sarcopenic and obese mice exposed to hyperoxia, oxidant stress and mitochondrial DNA fragmentation increase without a concomitant change in MQC to maintain a healthy and functional mitochondrial network. Suppression of HO-1 may be a mechanism for these changes during periods of hyperoxic stress in sarcopenia and obesity that contribute to poor outcomes in critical illness.

This work was supported by the Developing Research Excellence in Anesthesia Management Innovation Grant (2021).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.