Parental cardiorespiratory fitness influences early life energetics and metabolic health

Abstract

High cardiorespiratory fitness (CRF) is associated with a reduced risk of metabolic disease and is linked to superior mitochondrial respiratory function. This study investigated how intrinsic CRF affects bioenergetics and metabolic health in adulthood and early life. Adult rats selectively bred for low and high running capacity [low capacity runners (LCR) and high capacity runners (HCR), respectively] underwent metabolic phenotyping before mating. Weanlings were evaluated at 4-6 wk of age, and whole body energetics and behavior were assessed using metabolic cages. Mitochondrial respiratory function was assessed in permeabilized tissues through high-resolution respirometry. Proteomic signatures of adult and weanling tissues were determined using mass spectrometry. The adult HCR group exhibited lower body mass, improved glucose tolerance, and greater physical activity compared with the LCR group. The adult HCR group demonstrated higher mitochondrial respiratory capacities in the soleus and heart compared with the adult LCR group, which coincided with a greater abundance of proteins involved in lipid catabolism. HCR and LCR weanlings had similar body mass, but HCR weanlings displayed reduced adiposity. In addition, HCR weanlings exhibited better glucose tolerance and higher physical activity levels than LCR weanlings. Higher respiratory capacities were observed in the soleus, heart, and liver tissues of HCR weanlings compared with LCR weanlings, which were not owed to greater mitochondrial content. Proteomic analyses indicated a greater potential for lipid oxidation in the contractile muscles of HCR weanlings. In conclusion, offspring born to parents with high CRF possess an enhanced capacity for lipid catabolism and oxidative phosphorylation, thereby influencing metabolic health. These findings highlight that intrinsic CRF shapes the bioenergetic phenotype with implications for metabolic resilience in early life.NEW & NOTEWORTHY Inherited cardiorespiratory fitness (CRF) influences early life bioenergetics and metabolic health. Higher intrinsic CRF was associated with reduced adiposity and improved glucose tolerance in early life. This metabolic phenotype was accompanied by greater mitochondrial respiratory capacity in skeletal muscle, heart, and liver tissue. Proteomic profiling of these three tissues further revealed potential mechanisms linking inherited CRF to early life metabolism.

Keywords: aerobic capacity; metabolism; mitochondria; proteomics.

Graphical abstract

Figure 1.

Inherited cardiorespiratory fitness (CRF) influences whole body energetics and metabolic health in early life. A: body mass. n = 124 low capacity runners (LCR; 46% male and 54% female) and n = 85 high capacity runners (HCR; 55% male and 45% female). B: absolute lean body mass. n = 124 LCR (46% male and 54% female) and n = 94 HCR (54% male and 46% female). C: absolute fat mass. n = 124 LCR (46% male and 54% female) and n = 94 HCR (54% male and 46% female). D: blood glucose responses to an intraperitoneal glucose tolerance test. E: glucose area under the curve (AUC). F: change in blood glucose (120–0 min). n = 51 LCR (45% male and 55% female) and n = 43 HCR (49% male and 51% female) for D–F. G: body mass-adjusted total energy expenditure. H: body mass-adjusted basal energy expenditure. I: body mass-adjusted food intake. J: body mass-adjusted peak activity energy expenditure. K: all meters. L: sedentary time (% of total time). n = 16/group (50% male and 50% female) for G–L. An unpaired t test was used for all comparisons except for D, where a mixed-effects model (REML) and Šídák’s multiple-comparisons test were used. *P value obtained from an unpaired t test. All data are presented as means ± SD. n denotes animal number per group. REML, restricted maximum likelihood.

Figure 2.

Inherited cardiorespiratory fitness (CRF) influences mitochondrial respiratory capacity in early life. Mass-specific rates of oxygen consumption (Jo₂) during a substrate, uncoupler, and inhibitor titration protocol in permeabilized soleus muscle (A), cardiac muscle (B), and liver tissue (C). n = 44 low capacity runners (LCR; 48% male and 52% female) and n = 33 high capacity runners (HCR; 45% male and 55% female) for A, n = 39 LCR (49% male and 51% female) and n = 33 HCR (45% male and 55% female) for B, and n = 37 LCR (43% male and 57% female) and n = 29 HCR (52% male and 48% female) for C. E, electron transfer capacity; L, leak; P, OXPHOS capacity; PMGS, pyruvate (5 mM), malate (2 mM), glutamate (10 mM), and succinate (10 mM). An unpaired t test was used for all comparisons. All data are presented as means ± SD. n denotes animal number per group.

Figure 3.

Early life proteomic signatures diverge based on inherited cardiorespiratory fitness (CRF). A–C: volcano plots comparing the log₂ fold change in protein abundance [high capacity runner (HCR) weanlings vs. low capacity runner (LCR) weanlings] against log₁₀ false discovery rate-adjusted P values in soleus, heart, and liver tissue. n = 13 LCR (46% male and 54% female) and n = 10 HCR (50% male and 50% female) for A–C. D and E: Venn diagrams of soleus and heart proteins commonly more or less abundant in HCR weanlings than in LCR weanlings. Proteins are labeled by gene name. F and G: Western blot analyses of ACADSB protein levels in soleus (F) and heart tissue (G) of weanlings. n = 8/group for F and G. An unpaired t test was used for F and G. Data shown in F and G are means ± SD. ACADSB, short/branched-chain-specific acyl-CoA dehydrogenase. n denotes animal number per group.

Figure 4.

Gut microbiota composition diverges with intrinsic cardiorespiratory fitness (CRF) in early life. A: relative abundance of species at the phylum level in colon of low capacity runner (LCR) and high capacity runner (HCR) weanlings. B: Desulfobacterota counts. C: α diversity indexes, including Faiths Phylogenetic diversity (PD), Shannon index, and total observed taxa [i.e., species richness (SR)]. D: β diversity was assessed with unweighted Unifrac distances and visualized with Principal Coordinate Analysis (PCoA). Statistical significance was determined with PERMANOVA. n = 19 LCR and n = 21 HCR for A–D. PERMANOVA, permutational multivariate ANOVA. n denotes animal number per group.