Endocrinol Metab.  2022 Aug;37(4):630-640. 10.3803/EnM.2022.1430.

High Cardiorespiratory Fitness Protects against Molecular Impairments of Metabolism, Heart, and Brain with Higher Efficacy in Obesity-Induced Premature Aging

• Pantiya P
• Thonusin C
• Sumneang N
• Ongnok B
• Chunchai T
• Kerdphoo S
• Jaiwongkam T
• Arunsak B
• Siri-Angkul N
• Sriwichaiin S
• Chattipakorn N
• Chattipakorn SC

• KMID: 2532863
• DOI: http://doi.org/10.3803/EnM.2022.1430

Abstract

Background
High cardiorespiratory fitness (CRF) protects against age-related diseases. However, the mechanisms mediating the protective effect of high intrinsic CRF against metabolic, cardiac, and brain impairments in non-obese versus obese conditions remain incompletely understood. We aimed to identify the mechanisms through which high intrinsic CRF protects against metabolic, cardiac, and brain impairments in non-obese versus obese untrained rats.
Methods
Seven-week-old male Wistar rats were divided into two groups (n=8 per group) to receive either a normal diet or a highfat diet (HFD). At weeks 12 and 28, CRF, carbohydrate and fatty acid oxidation, cardiac function, and metabolic parameters were evaluated. At week 28, behavior tests were performed. At the end of week 28, rats were euthanized to collect heart and brain samples for molecular studies.
Results
The obese rats exhibited higher values for aging-related parameters than the non-obese rats, indicating that they experienced obesity-induced premature aging. High baseline CRF levels were positively correlated with several favorable metabolic, cardiac, and brain parameters at follow-up. Specifically, the protective effects of high CRF against metabolic, cardiac, and brain impairments were mediated by the modulation of body weight and composition, the lipid profile, substrate oxidation, mitochondrial function, insulin signaling, autophagy, apoptosis, inflammation, oxidative stress, cardiac function, neurogenesis, blood-brain barrier, synaptic function, accumulation of Alzheimer’s disease-related proteins, and cognition. Interestingly, this effect was more obvious in HFD-fed rats.
Conclusion
The protective effect of high CRF is mediated by the modulation of several mechanisms. These effects exhibit greater efficacy under conditions of obesity-induced premature aging.

Keyword

Cardiorespiratory fitness; Metabolic syndrome; Cardiovascular diseases; Neurodegenerative diseases; Obesity; Aging, premature

Figure

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  Fig. 1. Cardiorespiratory fitness (CRF) and plasma soluble-receptor for advanced glycation end product (sRAGE) protein expression at baseline (week 12) versus follow-up (week 28). (A) CRF, (B) plasma sRAGE protein expression (n=8 per group). The CRF level is reported as running distance. Data are reported as mean±standard error of the mean (SEM). The values on the top of each bar represent mean±SEM values of CRF levels. ND, normal diet; HFD, high-fat diet. aP<0.05 when compared to baseline within the same group (week 12).

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  Fig. 2. Cardiorespiratory fitness (CRF) and plasma soluble-receptor for advanced glycation end product (sRAGE) protein expression in normal diet (ND)-fed rats versus high-fat diet (HFD)-fed rats. (A) CRF, (B) plasma sRAGE protein expression (n=8 per group; week 12=baseline; week 28=follow-up). The CRF level is reported as running distance. Data are reported as mean±standard error of the mean (SEM). The values on the top of each bar represent mean±SEM values of CRF levels. aP<0.05 when compared to ND-fed rats at the same time point.

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  Fig. 3. Cardiorespiratory fitness (CRF) at baseline is positively correlated with CRF at follow-up and food intake. The scatter plots display (A) the correlation between CRF at baseline (week 12) and follow-up (week 28), and (B) the correlation between CRF at baseline (week 12) and average food intake (B) (n=8 per group). The CRF level is reported as running distance. Data are reported as r values. ND, normal diet; HFD, high-fat diet. aP<0.05.

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  Fig. 4. The effects of cardiorespiratory fitness (CRF) at baseline on metabolic parameters. Heatmap displaying correlations between CRF at baseline (week 12) and metabolic parameters at follow-up (week 28); correlations between CRF at baseline (week 12) and the absolute change (Δ) of metabolic parameters from baseline to follow-up (value at week 28–value at week 12) (n=8 per group). The CRF level is reported as running distance. Data are reported as r values. FAO, fatty acid oxidation rate; CHOO, carbohydrate oxidation rate; HOMA-IR, homeostatic model assessment for insulin resistance; HDL, high density lipoprotein; LDL, low density lipoprotein; ND, normal diet; HFD, high-fat diet. aP<0.05.

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  Fig. 5. The effects of cardiorespiratory fitness (CRF) at baseline on cardiac parameters. (A) Heatmap displaying: correlations between CRF at baseline (week 12) and cardiac parameters at follow-up (week 28); correlations between CRF at baseline (week 12) and the absolute change (Δ) of cardiac function from baseline to follow-up (value at week 28–value at week 12). (B) Representative pictures of apoptotic cell death in left ventricular tissue (n=8 per group). The CRF level is reported as running distance. Data are reported as r values. ROS, reactive oxygen species; CPT1, carnitine palmitoyltransferase I; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1α; p-AMPK, phosphorylated-activated protein kinase; AMPK, activated protein kinase; p-IRS, phosphorylated-insulin receptor substrate 1; IRS, insulin receptor substrate 1; MFN1, mitofusin 1; MFN2, mitofusin 2; OPA1, optic atrophy 1; p-DRP1ser616, phosphorylated-dynamin-related at serine616; DRP1, dynamin-related protein 1; PINK1, PTEN-induced kinase 1; LC3-II, light chain 3-II; Bax/Bcl, Bcl-2-associated X protein/B-cell lymphoma; GPX4, glutathione peroxidase 4; SOD2, superoxide dismutase 2; MDA, malondialdehyde; TNF-α, tumor necrosis factor-α; p-NFκB, phosphorylated-nuclear factor kappa-light-chain-enhancer of activated B cells; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; sRAGE, soluble-receptor for advanced glycation end product; LVEF, left ventricular ejection fraction; FS, fractional shortening; E/A, early to late ventricular filling velocity; LF/HF, lower frequency/high frequency; ND, normal diet; HFD, high-fat diet. aP<0.05.

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  Fig. 6. The effects of cardiorespiratory fitness (CRF) at baseline on brain parameters. (A) Heatmap displaying correlations between CRF at baseline (week 12) and brain parameters at follow-up (week 28). (B) Representative pictures of apoptotic cell death at CA1 of the hippocampus (n=8 per group). The CRF level is reported as running distance. Data are reported as r values. PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1α; p-AMPK, phosphorylated-activated protein kinase; AMPK, activated protein kinase; MFN1, mitofusin 1; MFN2, mitofusin 2; OPA1, optic atrophy 1; p-DRP1ser616, phosphorylated-dynamin-related at serine616; DRP1, dynamin-related protein 1; PINK1, PTEN-induced kinase 1; LC3-II, light chain 3-II; Bax/Bcl, Bcl-2-associated X protein/B-cell lymphoma; GPX4, glutathione peroxidase 4; SOD2, superoxide dismutase 2; ROS, reactive oxygen species; MDA, malondialdehyde; TNF-α, tumor necrosis factor-α; p-NFκB, phosphorylated-nuclear factor kappa-light-chain-enhancer of activated B cells; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; PSD-95, postsynaptic density protein 95; p-TrκB, phosphorylated-tropomyosin receptor kinase B; TrκB, tropomyosin receptor kinase B; BDNF, brain-derived neurotrophic factor; DCX, doublecortin; p-Tau, phosphorylated-Tau; APP, amyloid-beta precursor protein; Aβ, amyloid β; BACE-1, beta-site amyloid precursor protein cleaving enzyme 1; sRAGE, soluble-receptor for advanced glycation end product; ND, normal diet; HFD, high-fat diet. aP<0.05.

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