Enhanced Gastrocnemii Aerobmic Metabolism in Aged Male Rats Following Postnatal Hyperoxia
Authors: Tetri Laura Hope , Braun Rudolf K , Haraldsdottir Kristin , Pegelow David F , Gross Kara N , Eldridge Marlowe W 
Published: November 2023

Background

12% of infants are born prematurely, and many require oxygen therapy and ventilation. Although life sustaining, oxygen therapy carries long‐term consequences. These children and young adults are at increased risk for metabolic disorders, including decreased insulin sensitivity, metabolic syndrome, and cardiovascular disease. However, there is little understanding of the effects of postnatal hyperoxia on skeletal muscle. We hypothesized that aged rats exposed to postnatal hyperoxia would have persistent alterations in expression of glucose metabolic enzymes and mitochondrial markers within the gastrocnemius.

Methods

Sprague‐Dawley rats were exposed to either hyperoxia (HYP) (85% oxygen; n=13; 6 males) or normoxia (NORM) (21% oxygen, n=8; 3 males) for the first 14 days of life. Following these exposures, the rats were aged to one year in room air. At one year, the animals were sacrificed and the gastrocnemii were flash frozen in liquid nitrogen. Protein expression was analyzed by western blot. Statistics were done by two‐way ANOVA to compare male and female of both NORM and HYP, with Tukey's for multiple comparisons.

Results

At one year, there was a trend towards increased body mass index in the HYP rats compared to NORM (6.6% increase, p=0.095). There was a decrease in gastrocnemii to body weight ratio in the HYP rats compared to NORM (8.7% decrease, p=0.03). GLUT1, a constitutively present glucose transporter, was upregulated in HYP female rats (45.7% increase compared to NORM female), but unchanged in HYP males compared to NORM males (p<0.0001 for interaction). In male HYP rats, phosphofructokinase 1 was upregulated compared to NORM males but expression in female HYP rats was unchanged compared to NORM females (40.0% increase, p=0.03 for the interaction). No other measured glycolytic enzymes were altered in any groups, including hexokinase 1, PDH, phosphoPDH ratio, and LDHA (p>0.05 for all). In the HYP male rats, citrate synthase had a trend towards increase and VDAC1 was higher compared to NORM males (32.3% and 29.8% increases, p=0.11 and p=0.045 for male NORM to male HYP, with p=0.09 and p=0.07 for interaction, respectively). However, the HYP males were not different from NORM or HYP females. In female HYP rats, there was no change in markers of mitochondrial quantity, but OPA‐1, responsible for mitochondrial fusion and cristae formation, was significantly upregulated compared to NORM females (48.8% increase, p=0.04)

Conclusions

There were significant alterations in metabolic enzyme and mitochondrial marker expression in skeletal muscle of postnatal HYP rats aged to one year. Males tend to express a more aerobic profile with increased citrate synthase and VDAC1, markers of mitochondrial quantity. This shift towards a more aerobic and mitochondria‐dependent metabolic profile resembles the state of normoxia female gastrocnemii, and may represent a decreased potential for power output, but an increased potential for aerobic metabolism.

Support or Funding Information

Funding source: NHLBI, R01 HL115061‐03, Suppl (Eldridge) & NHLBI, R01 HL115061 (Eldridge)