Excessive positive energy balance is a major factor leading to obesity. The ability to alter the appetite-regulating hormones leptin, adiponectin, and ghrelin may help decrease excessive energy intake. Exercise and exposure to extreme temperatures can independently affect these appetiteregulating hormones. PURPOSE: To determine the effect of exercising in different environmental conditions on the circulating concentrations of leptin, adiponectin, and ghrelin. METHODS: Eleven recreationally-trained male participants completed 3 separate 1 h cycling bouts at 60% W max in hot, cold, and room temperature conditions (33 C, 7 C, 20 C), followed by a 3 h recovery at room temperature. Blood was drawn pre-exercise, post-exercise, and 3 h post-exercise. Hematocrit and hemoglobin were measured to account for change in plasma volume. RESULTS: Leptin concentrations were lower at post and 3 h post-exercise compared with pre-exercise, with and without correction for plasma volume shifts, regardless of temperature (p < 0.05). Adiponectin was higher post-exercise compared with pre-exercise (p D 0.021) but not 3 h post-exercise (p D 0.084) without correction for plasma volume shifts. However, adiponectin concentrations were not different at any time point when plasma volume shifts were accounted for (p > 0.05). Total ghrelin and acylated ghrelin concentrations were not affected at post and 3 h post-exercise compared with pre-exercise, with and without correcting for plasma volume shifts, regardless of ambient temperature (p > 0.05). No differences in leptin, adiponectin, or ghrelin were found between trials (p > 0.05). CONCLUSION: Temperature does not affect the circulating concentrations of appetiteregulating hormones during an acute bout of endurance exercise.

Many human diseases lead to a loss of skeletal muscle metabolic function and mass. Local and environmental temperature can modulate the exercise-stimulated response of several genes involved in mitochondrial biogenesis and skeletal muscle function in a human model. However, the impact of environmental temperature, independent of exercise, has not been addressed in a human model. Thus, the purpose of this study was to compare the effects of exposure to hot, cold, and room temperature conditions on skeletal muscle gene expression related to mitochondrial biogenesis and muscle mass. METHODS Recreationally trained male subjects (n=12) had muscle biopsies taken from the vastus lateralis before and after 3 h exposure to hot (33 °C), cold (7 °C), or room temperature (20 °C) conditions. RESULTS Temperature had no effect on most of the genes related to mitochondrial biogenesis, myogenesis, or proteolysis (p > 0.05). Core temperature was significantly higher in hot and cold environments compared to room temperature (37.2 ± 0.1 °C, p = 0.001; 37.1 ± 0.1 °C, p = 0.013; 36.9 ± 0.1 °C, respectively). Whole body oxygen consumption was also significantly higher in hot and cold compared to room temperature (0.38 ± 0.01 L·min−1, p < 0.001; 0.52 ± 0.03 L·min−1, p < 0.001; 0.35 ± 0.01 L·min−1, respectively). CONCLUSIONS These data show that acute temperature exposure alone does not elicit significant changes in skeletal muscle gene expression. When considered in conjunction with previous research, exercise appears to be a necessary component to observe gene expression alterations between different environmental temperatures in humans.

The skeletal muscle research field generally accepts that nuclei in skeletal muscle fibers (i.e., myonuclei) are post-mitotic and unable to proliferate. Because our deuterium oxide (D2O) labeling studies showed DNA synthesis in skeletal muscle tissue, we hypothesized that resident myonuclei can replicate in vivo. To test this hypothesis, we used a mouse model that temporally labeled myonuclei with GFP followed by D2O labeling during normal cage activity, functional overload, and with satellite cell ablation. During normal cage activity, we observed deuterium enrichment into myonuclear DNA in 7 out of 7 plantaris (PLA), 6 out of 6 tibialis anterior (TA), 5 out of 7 gastrocnemius (GAST) and 7 out of 7 quadriceps (QUAD). The average fractional synthesis rates (FSR) of DNA in myonuclei were: 0.0202 ± 0.0093 in PLA, 0.0239 ± 0.0040 in TA, 0.0076 ± 0. 0058 in GAST, and 0.0138 ± 0.0039 in QUAD, while there was no replication in myonuclei from EDL. These FSR values were largely reproduced in the overload and satellite cell ablation conditions although there were higher synthesis rates in the overloaded PLA muscle. We further provided evidence that myonuclear replication is through endoreplication that results in polyploidy. These novel findings contradict the dogma that skeletal muscle nuclei are post-mitotic and open potential avenues to harness the intrinsic replicative ability of myonuclei for muscle maintenance and growth.

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Introduction: Notch proteins are a single-pass type 1 transmembrane protein that regulates cellular proliferation and inhibits myogenic differentiation. Numb and Numb-Like are adaptor proteins. Among their functions is control of cell fate determination and progression of cell differentiation via inhibition of Notch. While no role for Numb-Like has been found in cells of the myogenic lineage, Numb promotes myogenic differentiation of satellite cells. The roles these proteins in human skeletal muscle in response to exercise-induced muscle damage have yet to be examined. Purpose: The purpose of this investigation is to examine changes in the expression of Notch, Numb and Numb-Like in human skeletal muscle after a bout of muscle damage via eccentric exercise. Methods: Seventeen, recreationally trained, male subjects signed an informed consent approved by The University of Kansas's Institutional Review Board and were randomly assigned to one of two groups: a control group (n = 5) or a damage group (n = 12). Subjects completed a one repetition maximum (1RM) in leg extension followed by seven sets of ten repetitions of eccentric leg extension at %120 of 1RM with a two minutes of rest period between sets. Four muscle biopsies of the vastus lateralis were collected at baseline, 3-hours post-two days post-, and five days post-muscle damage and analyzed utilizing Western blot and quantitative reverse transcription polymerase chain reaction analyses. The results were analyzed using two separate analyses. The first being a 2X3 (Group X Time) Two-Way Repeated Measures ANOVA for the baseline measures, two days post-and five days post-muscle damage time points with the exclusion of the 3-hour post damage time point. The second being a One-Way Repeated Measures ANOVA with only the experimental group. Results: There were no significant main effects of time for the damage group with the inclusion of the three hour time point from baseline for Numb (p > 0.05: 3-Hour p = 0.22, Day 2 p = 0.89, and Day 5 p = 0.17) and Numb-Like (3-Hour p = 0.63, iv Day 2 p = 0.30, and Day 5 p = 0.77). Additionally, no significant differences in mRNA expression were observed for Numb between groups two days post-and five days post-muscle damage for Numb (p = 0.13 and p = 0.74, respectively) and Numb-Like (p = 0.28 and p = 0.60, respectively).There was no significant main effect of time for Notch1 among the damage group with the inclusion of the three-hour time point from baseline (3-Hour p = 0.84, Day 2 p = 0.28, and Day 5 p = 0.20). Additionally, no significant differences in mRNA expression were observed for Notch1 between groups at two days post-muscle damage (p = 0.56). However, there was a significant increase in Notch1 at five days post-muscle damage between the exercise group (1.91 ± 1.29 fold change) and the control group (0.52 ± 0.38 fold change) from baseline measures (p = 0.04). Conclusion:Numb and Numb-Like expression was unaltered post-muscle damage, while Notch mRNA expression was increased after exercise-induced muscle damage. These resu...

The purpose of this study was to determine the effects of exercise in hot, cold, and temperate environments on plasma interleukin-6 (IL-6). Eleven recreationally trained males (age 5 25 ¡ 4 years, height 5 178 ¡ 5 cm, weight 5 79.4 ¡ 13.5 kg, body fat 5 14.7 ¡ 3.6%, VO 2 peak 5 54.6 ¡ 11.5 ml kg 21 min 21) performed a 1 hr cycling bout in hot (33˚C), cold (7˚C), and temperate (20˚C) environments at 60% of W max followed by 3 hr of supine recovery in temperate conditions. Expired gases were measured every 15 min during exercise and once every hour during recovery. Heart rate was continuously measured throughout the trials. Blood samples were obtained from the antecubital vein pre-exercise, immediately post-exercise, and 3 hr post-exercise. Blood samples were analyzed for plasma concentrations of IL-6 using a commercial ELISA kit. Plasma IL-6 concentrations were significantly higher immediately post-exercise (14.8 ¡ 1.6 pg ml 21 , p 5 0.008) and 3 hr post-exercise (14.8 ¡ 0.9 pg ml 21, p 5 0.018) compared to pre-exercise (11.4 ¡ 2.4 pg ml 21), across all trials. There were no differences in plasma IL-6 concentrations (p 5 0.207) between temperature conditions. Oxygen consumption and heart rate were higher and respiratory exchange ratio was lower in the hot compared to other conditions (p , 0.05). These data indicate that the temperature in which exercise occurs does not affect acute plasma IL-6 response despite differences in metabolic state.

The skeletal muscle research field generally accepts that nuclei in skeletal muscle fibers (i.e., myonuclei) are post-mitotic and unable to proliferate. Because of previous data indicating DNA synthesis in skeletal muscle tissue, we hypothesized that skeletal muscle resident myonuclei can replicate in vivo. To test this hypothesis, we used a mouse model that facilitated temporal labeling with GFP following by deuterium oxide (D2O) labeling during normal cage activity, overload, and with satellite cell ablation. During normal cage activity, we observed deuterium enrichment into myonuclear DNA in 7 out of 7 plantaris (PLA), 6 out of 6 tibialis anterior (TA), 5 out of 7 gastrocnemius (GAST), and 7 out of 7 quadriceps (QUAD). The average fraction synthesis rates (FSR) of replicating myonuclei were: 0.0202 plus-or-minus sign 0.0093 in PLA, 0.0239 plus-or-minus sign 0.0040 in TA, 0.0076 plus-or-minus sign 0. 0058 in GAST, and 0.0138 plus-or-minus sign 0.0039 in QUAD, while EDL appeared not to have replicative myonuclei. These values were largely reproduced in our other conditions with increased rates in an overloaded plantaris muscle. We further showed that these replication events potentially resulted in polyploidy. With our new approach, we unambiguously demonstrated that mammalian myonuclei can replicate in vivo. The amounts of DNA synthesis differed by muscle and increased with mechanical overload. It also appears that there is endoreplication of resident myonuclei that results in polyploidy. These findings contradict the dogma that skeletal muscle myocytes are post-mitotic and open potential avenues to harness the intrinsic replicative ability of the cell for muscle maintenance and growth.

The antidiabetic medication metformin has been proposed to be the first drug tested to target aging and extend healthspan in humans. While there is extensive epidemiological support for the health benefits of metformin in patient populations, it is not clear if these protective effects apply to those free of age-related disease. Our previous data in older adults without diabetes suggest a dichotomous change in insulin sensitivity and skeletal muscle mitochondrial adaptations after metformin treatment when co-prescribed with exercise. Those who entered the study as insulin sensitive had no change to detrimental effects while those who were insulin resistant had positive changes. The objective of this clinical trial is to determine if 1) antecedent metabolic health and 2) skeletal muscle mitochondrial remodeling and function mediate the positive or detrimental effects of metformin monotherapy, independent of exercise, on the metabolism and biology of aging. In a randomized, double blind clinical trial, adults free of chronic disease (n=148, 40-75 years old) are stratified as either insulin sensitive or resistant based on HOMA-IR (≤2.2 or ≥2.5) and take 1500 mg/day of metformin or placebo for 12 weeks. Hyperinsulinemic-euglycemic clamps and skeletal muscle biopsies are performed before and after 12 weeks to assess primary outcomes of peripheral insulin sensitivity and mitochondrial remodeling and function. Findings from this trial will identify clinical characteristics and cellular mechanisms involved in modulating the effectiveness of metformin treatment to target aging that could inform larger phase 3 clinical trials aimed at testing aging as a treatment indication for metformin.