Abstract
Age-associated declines in aerobic capacity promote the development of various metabolic diseases. In rats selectively bred for high/low intrinsic aerobic capacity, greater aerobic capacity reduces susceptibility to metabolic disease while increasing longevity. However, little remains known how intrinsic aerobic capacity protects against metabolic disease, particularly with aging. Here, we tested the effects of aging and intrinsic aerobic capacity on systemic energy expenditure, metabolic flexibility and mitochondrial protein synthesis rates using 24-month-old low-capacity (LCR) or high-capacity runner (HCR) rats. Rats were fed low-fat diet (LFD) or high-fat diet (HFD) for eight weeks, with energy expenditure (EE) and metabolic flexibility assessed utilizing indirect calorimetry during a 48 h fast/re-feeding metabolic challenge. Deuterium oxide (D2O) labeling was used to assess mitochondrial protein fraction synthesis rates (FSR) over a 7-day period. HCR rats possessed greater EE during the metabolic challenge. Interestingly, HFD induced changes in respiratory exchange ratio (RER) in male and female rats, while HCR female rat RER was largely unaffected by diet. In addition, analysis of protein FSR in skeletal muscle, brain, and liver mitochondria showed tissue-specific adaptations between HCR and LCR rats. While brain and liver protein FSR were altered by aerobic capacity and diet, these effects were less apparent in skeletal muscle. Overall, we provide evidence that greater aerobic capacity promotes elevated EE in an aged state, while also regulating metabolic flexibility in a sex-dependent manner. Modulation of mitochondrial protein FSR by aerobic capacity is tissue-specific with aging, likely due to differential energetic requirements by each tissue.
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Acknowledgements
Edziu Franczak was involved in the investigation, statistical analysis, visualization, and writing of the original draft. Adrianna Maurer was involved in the investigation, methodology, and writing-review and editing. Vivien Csikos Drummond, Emily Wells, Madi Wenger, Frederick F. Peelor III, Abby Crosswhite, and Benjamin F. Miller were involved in the investigation, statistical analysis, visualization, and writing-review and editing, Colin S. McCoin and Benjamin A. Kugler were involved in the investigation and writing-review and editing. Steven L. Britton and Lauren G. Koch were involved in the development of rat models and writing-review. John P. Thyfault was involved in the conceptualization, methodology, formal analysis, investigation, funding acquisition, and writing-review and editing.
Funding
This project was supported in part by National Institutes of Health R01DK121497 (JPT) and R01DK121497-03A1 Supplement (JPT), and the National Institute of General Medical Sciences S10OD028598 (JPT). The HCR/LCR rat models were funded by National Institutes of Health Office of Research Infrastructure Programs Grant P40OD-021331 and 3P40OD021331-06S1 (LGK and SLB).
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11357_2023_985_MOESM1_ESM.tiff
Supplemental Fig. 1. Representative images of hepatic triglyceride storage. Representative images of Hematoxylin and eosin staining on liver sections in male and female HCR rats fed either a HFD or LFD (TIFF 163854 KB)
11357_2023_985_MOESM2_ESM.tiff
Supplemental Fig. 2. Skeletal muscle and liver correlations between energy expenditure and mitochondrial protein fractional synthesis rates. Correlations between total EE and mitochondrial protein FSR in (a) male and (b) female gastrocnemius muscle, soleus (c, d) and liver (e, f) (TIFF 4004 KB)
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Franczak, E., Maurer, A., Drummond, V.C. et al. Divergence in aerobic capacity and energy expenditure influence metabolic tissue mitochondrial protein synthesis rates in aged rats. GeroScience 46, 2207–2222 (2024). https://doi.org/10.1007/s11357-023-00985-1
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DOI: https://doi.org/10.1007/s11357-023-00985-1