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In a 77-year-old former world-record-holding male marathoner (2:08:33.6), this study sought to investigate the impact of lifelong intensive endurance exercise on cardiac structure, function, and the trajectory of functional capacity (determined by maximal oxygen consumption, V̇ o 2max) throughout the adult lifespan. As a competitive runner, our athlete (DC) reported performing up to 150–300 miles/wk of moderate-to-vigorous exercise and sustained 10–15 h/wk of endurance exercise after retirement from competition. DC underwent maximal cardiopulmonary exercise testing in 1970 (aged 27 yr), 1991 (aged 49 yr), and 2020 (aged 77 yr) to determine V̇ o 2max. At his evaluation in 2020, DC also underwent comprehensive cardiac assessments including resting echocardiography, and resting and exercise cardiac magnetic resonance to quantify cardiac structure and function at rest and during peak supine exercise. DC's V̇ o 2max showed minimal change from 27 yr (69.7 mL/kg/min) to 49 yr (68.1 mL/kg/min), although it eventually declined by 36% by the age of 77 yr (43.6 mL/kg/min). DC's V̇ o 2max at 77 yr, was equivalent to the 50th percentile for healthy 20- to 29-yr-old males and 2.4 times the requirement for maintaining functional independence. This was partly due to marked ventricular dilatation (left-ventricular end-diastolic volume: 273 mL), which facilitates a large peak supine exercise stroke volume (200 mL) and cardiac output (22.2 L/min). However, at the age of 78 yr, DC developed palpitations and fatigue and was found to be in atrial fibrillation requiring ablation procedures to revert his heart to sinus rhythm. Overall, this life study of a world champion marathon runner exemplifies the substantial benefits and potential side effects of many decades of intense endurance exercise. NEW & NOTEWORTHY: This life study of a 77-yr-old former world champion marathon runner exemplifies the impact of lifelong high-volume endurance exercise on functional capacity (V̇ o 2max equivalent to a 20- to 29-yr-old), partly due to extreme ventricular remodeling that facilitates a large cardiac output during exercise despite reduced maximal heart rate. Although it is possible that this extreme remodeling may contribute to developing atrial fibrillation, the net benefits of extreme exercise throughout this athlete's lifespan favor increased health span and expected longevity. [ABSTRACT FROM AUTHOR]

Women exhibit an enhanced capability for lipid metabolism during endurance exercise compared with men. The underlying regulatory mechanisms behind this sex-related difference are not well understood but may comprise signaling through a myocyte enhancer factor 2 (MEF2) regulatory pathway. The primary purpose of this study, therefore, was to investigate the protein signaling of MEF2 regulatory pathway components at rest and during 90 min of bicycling exercise at 60% [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]in healthy, moderately trained men (n = 8) and women (n = 9) to elucidate the potential role of these proteins in substrate utilization during exercise. A secondary purpose was to screen for mRNA expression of MEF2 isoforms and myogenic regulatory factor (MRF) family members of transcription factors at rest and during exercise. Muscle biopsies were obtained before and immediately after exercise. Nuclear AMP-activated protein kinase-[alpha] ([alpha]AMPK) [Thr.sup.172] (P < 0.001), histone deacetylase 5 (HDAC5) [Ser.sup.498] (P < 0.001), and MEF2 Thr (P < 0.01) phosphorylation increased with exercise. No significant sex differences were observed at rest or during exercise. At rest, no significant sex differences were observed in mRNA expression of the measured transcription factors, mRNA for transcription factors MyoD, myogenin, MRF4, MEF2A, MEF2C, MEF2D, and peroxisome proliferator-activated receptor-3, coactivator Is (PGCI[alpha]) were significantly upregulated by exercise. Of these, MEF2A mRNA increased 25% specifically in women (P < 0.05), whereas MEF2D mRNA tended to increase in men (P = 0.11). Although minor sex differences in mRNA expression were observed, the main finding of the present study was the implication of a joint signaling action of AMPK, HDAC5, and PGCI[alpha] on MEF2 in the immediate regulatory response to endurance exercise. This signaling response was independent of sex. skeletal muscle; myogenic regulatory factor; AMP-activated protein kinase; histone deacetylase 5; peroxisome proliferator-activated receptor-[gamma] coactivator 1[alpha]

As substrate for evaluation of metabolic diseases, we developed novel rat models that contrast for endurance exercise capacity. Through two-way artificial selection, we created rodent phenotypes of intrinsically low-capacity runners (LCR) and high-capacity runners (HCR) that also differed markedly for cardiovascular and metabolic disease risk factors. Here, we determined skeletal muscle proteins with putative roles in lipid and carbohydrate metabolism to better understand the mechanisms underlying differences in whole body substrate handling between phenotypes. Animals (generation 16) differed for endurance running capacity by 295%. LCR animals had higher resting plasma glucose (6.58 [+ or -] 0.45 vs. 6.09 [+ or -] 0.45 mmol/l), insulin (0.48 [+ or -] 0.03 vs. 0.32 [+ or -] 0.02 ng/ml), nonesterified fatty acid (0.57 [+ or -] 0.14 v 0.35 [+ or -] 0.05 mM), and triglyceride (TG; 0.47 [+ or -] 0.11 vs. 0.25 [+ or -] 0.08 mmol/l) concentrations (all P < 0.05). Muscle TG (72.3 [+ or -] 14.7 vs. 38.9 [+ or -] 6.2 mmol/kg dry muscle wt; P < 0.05) and diacylglycerol (96 [+ or -] 28 vs. 42 [+ or -] 8 pmol/mg dry muscle wt; P < 0.05) contents were elevated in LCR vs. HCR rats. Accompanying the greater lipid accretion in LCR was increased fatty acid translocase/CD36 content (1,014 [+ or -] 80 vs. 781 [+ or -] 70 arbitrary units; P < 0.05) and reduced TG lipase activity (0.158 [+ or -] 0.0125 vs. 0.274 [+ or -] 0.018 mmol x [min.sup.-] x kg dry muscle [wt.sup.-1]; P < 0.05). Muscle glycogen, GLUT4 protein, and basal phosphorylation states of AMP-activated protein kinase-[[alpha].sub.1], AMP-activated protein kinase-[[alpha].sub.2], and acetyl-CoA carboxylase were similar in LCR and HCR. In conclusion, rats with low intrinsic aerobic capacity demonstrate abnormalities in lipid-handling capacity. These disruptions may, in part, be responsible for the increased risk of metabolic disorders observed in this phenotype. exercise capacity; insulin resistance; mitochondrial biogenesis; lipids doi: 10.1152/ajpendo.00702.2006

Five days of a high-fat diet while training, followed by 1 day of carbohydrate (CHO) restoration, increases rates of whole body fat oxidation and decreases CHO oxidation during aerobic cycling. The mechanisms responsible for these shifts in fuel oxidation are unknown but involve up- and downregulation of key regulatory enzymes in the pathways of skeletal muscle fat and CHO metabolism, respectively. This study measured muscle PDH and HSL activities before and after 20 min of cycling at 70% V[O.sub.2 peak] and 1 min of sprinting at 150% peak power output (PPO). Estimations of muscle glycogenolysis were made during the initial minute of exercise at 70% V[O.sub.2 peak] and during the 1-min sprint. Seven male cyclists undertook this exercise protocol on two occasions. For 5 days, subjects consumed in random order either a high-CHO (HCHO) diet (10.3 g*[kg.sup.-1]*[day.sup.-1] CHO, or ~70% of total energy intake) or an isoenergetic high-fat (FAT-adapt) diet (4.6 g*[kg.sup.-]*[day.sup.-1] FAT, or 67% of total energy) while undertaking supervised aerobic endurance training. On day 6 for both treatments, subjects ingested an HCHO diet and rested before their experimental trials on day 7. This CHO restoration resulted in similar resting glycogen contents (FAT-adapt 873 [+ or -] 121 vs. HCHO 868 [+ or -] 120 [micro]mol glucosyl units/g dry wt). However, the respiratory exchange ratio was lower during cycling at 70% V[O.sub.2 peak] in the FAT-adapt trial, which resulted in an ~45% increase and an ~30% decrease in fat and CHO oxidation, respectively. PDH activity was lower at rest and throughout exercise at 70% V[O.sub.2 peak] (1.69 [+ or -] 0.25 vs. 2.39 [+ or -] 0.19 mmol*kg wet [wt.sup.-1]*[min.sup.-1]) and the 1-min sprint in the FAT-adapt vs. the HCHO trial. Estimates of glycogenolysis during the 1st min of exercise at 70% V[O.sub.2 peak] and the 1-min sprint were also lower after FAT-adapt (9.1 [+ or -] 1.1 vs. 13.4 [+ or -] 2.1 and 37.3 [+ or -] 5.1 vs. 50.5 [+ or -] 2.7 glucosyl units*kg dry [wt.sup.-l]*[min.sup.-1]). HSL activity was ~20% higher (P = 0.12) during exercise at 70% V[O.sub.2 peak] after FAT-adapt. Results indicate that previously reported decreases in whole body CHO oxidation and increases in fat oxidation after the FAT-adapt protocol are a function of metabolic changes within skeletal muscle. The metabolic signals responsible for the shift in muscle substrate use during cycling at 70% V[O.sub.2 peak] remain unclear, but lower accumulation of free ADP and AMP after the FAT-adapt trial may be responsible for the decreased glycogenolysis and PDH activation during sprinting. skeletal muscle metabolism; pyruvate dehydrogenase; substrate phosphorylation; fat oxidation; carbohydrate oxidation

The subcellular localization of insulin signaling proteins is altered by various stimuli such as insulin, insulin-like growth factor I, and oxidative stress and is thought to be an important mechanism that can influence intracellular signal transduction and cellular function. This study examined the possibility that exercise may also alter the subcellular localization of insulin signaling proteins in human skeletal muscle. Nine untrained males performed 60 min of cycling exercise (~67% peak pulmonary [O.sub.2] uptake). Muscle biopsies were sampled at rest, immediately after exercise, and 3 h postexercise. Muscle was fractionated by centrifugation into the following crude fractions: cytosolic, nuclear, and a high-speed pellet containing membrane and cytoskeletal components. Fractions were analyzed for protein content of insulin receptor, insulin receptor substrate (IRS)-1 and -2, p85 subunit of phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3 (GSK-3). There was no significant change in the protein content of the insulin signaling proteins in any of the crude fractions after exercise or 3 h postexercise. Exercise had no significant effect on the phosphorylation of IRS-1 [Tyr.sup.612] in any of the fractions. In contrast, exercise increased (P < 0.05) the phosphorylation of Akt [Ser.sup.473] and GSK-3[alpha]/[beta] [Ser.sup.9/21] in the cytosolic fraction only. In conclusion, exercise can increase phosphorylation of downstream insulin signaling proteins specifically in the cytosolic fraction but does not result in changes in the subcellular localization of insulin signaling proteins in human skeletal muscle. Change in the subcellular protein localization is therefore an unlikely mechanism to influence signal transduction pathways and cellular function in skeletal muscle after exercise. insulin receptor substrate; intracellular signaling pathway