The physiological impact of high?intensity interval training in octogenarians with comorbidities

BackgroundDeclines in cardiorespiratory fitness (CRF) and fat-free mass (FFM) with age are linked to mortality, morbidity and poor quality of life. High-intensity interval training (HIIT) has been shown to improve CRF and FFM in many groups, but its efficacy in the very old, in whom comorbidities are present is undefined. We aimed to assess the efficacy of and physiological/metabolic responses to HIIT, in a cohort of octogenarians with comorbidities (e.g. hypertension and osteoarthritis).MethodsTwenty-eight volunteers (18 men, 10 women, 81.2 ± 0.6 years, 27.1 ± 0.6 kg·m−2) with American Society of Anaesthesiology (ASA) Grade 2–3 status each completed 4 weeks (12 sessions) HIIT after a control period of equal duration. Before and after each 4 week period, subjects underwent body composition assessments and cardiopulmonary exercise testing. Quadriceps muscle biopsies (m. vastus lateralis) were taken to quantify anabolic signalling, mitochondrial oxidative phosphorylation, and cumulative muscle protein synthesis (MPS) over 4-weeks.ResultsIn comorbid octogenarians, HIIT elicited improvements in CRF (anaerobic threshold: +1.2 ± 0.4 ml·kg−1·min−1, P = 0.001). HIIT also augmented total FFM (47.2 ± 1.4 to 47.6 ± 1.3 kg, P = 0.04), while decreasing total fat mass (24.8 ± 1.3 to 24 ± 1.2 kg, P = 0.0002) and body fat percentage (33.1 ± 1.5 to 32.1 ± 1.4%, P = 0.0008). Mechanistically, mitochondrial oxidative phosphorylation capacity increased after HIIT (i.e. citrate synthase activity: 52.4 ± 4 to 67.9 ± 5.1 nmol·min−1·mg−1, P = 0.005; membrane protein complexes (C): C-II, 1.4-fold increase, P = 0.002; C-III, 1.2-fold increase, P = 0.03), as did rates of MPS (1.3 ± 0.1 to 1.5 ± 0.1%·day−1, P = 0.03). The increase in MPS was supported by up-regulated phosphorylation of anabolic signalling proteins (e.g. AKT, p70S6K, and 4E-BP1; all P < 0.05). There were no changes in any of these parameters during the control period. No adverse events were reported throughout the study.ConclusionsThe HIIT enhances skeletal muscle mass and CRF in octogenarians with disease, with up-regulation of MPS and mitochondrial capacity likely underlying these improvements. HIIT can be safely delivered to octogenarians with disease and is an effective, time-efficient intervention to improve muscle mass and physical function in a short time frame

IMPACT OF IN VITRO METFORMIN ON OFFSPRING MITOCHONDRIAL BIOENERGETICS WITH MATERNAL EXERCISE OR GESTATIONAL DIABETES

Ericka M. Biagioni, Nicholas T. Broskey. East Carolina University, Greenville, NC. BACKGROUND: The prevalence of gestational diabetes mellitus (GDM) is increasing, and offspring exposed to GDM in utero have an increased risk of long-term health consequences. Exercise has been shown to ameliorate conditions associated with metabolic dysfunction in part via improvements in mitochondrial function. Current data in rodent models of pregnant dams suggest these mitochondrial outcomes can be transferred from the mother to the developing fetus through exercise. However, when lifestyle modifications are not sufficient to treat GDM, metformin is commonly prescribed. Metformin freely crosses the placenta and reaches concentrations in fetal circulation that are equal to that of maternal circulation. Like exercise, metformin also elicits effects on the mitochondria by decreasing efficiency via decreases in the net proton motive force. Metformin has been shown to attenuate the mitochondrial adaptations from exercise when combined; however, this has not been tested in pregnancy. Umbilical cord derived mesenchymal stem cells (MSCs) give rise to several tissues originating from the fetal mesoderm and serve as a robust model of offspring cellular outcomes. The purpose of this study is to investigate the impact of in vitro metformin exposure on mitochondrial outcomes in MSCs that are from healthy women, who exercise or are exposed to metabolic disease in utero. METHODS: MSCs will be cultured from umbilical cord Wharton’s Jelly from pregnant women who were sedentary, exercised, or diagnosed with GDM and not on metformin. Cells from each group will be treated with media conditions containing metformin and without. Mitochondrial efficiency will be measured in permeabilized MSCs through a series of mitochondrial diagnostic assays that will measure the rate of oxygen consumption (JO2) and/or the rate of ATP generation (JATP) with the addition of various substrates, enzymes, and inhibitors. Statistical analysis will be performed in GraphPad Prism by using two-way ANOVA and presented as mean + SEM to determine differences between groups. ANTICIPATED RESULTS: We hypothesize that MSCs from sedentary, exercised, and GDM pregnancies that are treated with metformin in vitro will have lower mitochondrial efficiency compared to those not exposed to metformin within each respective group. These results will lead to further investigation into the impact of metformin treated GDM on offspring mitochondrial outcomes

INHERITABILITY OF THE “ATHLETE’S PARADOX”: THE IMPACT OF MATERNAL EXERCISE ON OFFSPRING SKELETAL MUSCLE HEALTH

Polina Krassovskaia, Nicholas T. Broskey. East Carolina University, Greenville, NC. BACKGROUND: Ectopic lipid in skeletal muscle (SM) has been linked to insulin resistance in individuals with metabolic diseases. The “Athlete’s Paradox” describes that individuals with metabolic diseases have high intramyocellular lipid content, which is associated with low insulin sensitivity, but athletes have a similarly high intramyocellular lipid content and high insulin sensitivity. Thus, exercise training increases the oxidative capacity of SM via increased oxidation of intramyocellular lipids concomitant with improvements in insulin sensitivity. Exercise during pregnancy as a mode of transferring the benefits of exercise to the developing fetus has gained traction and offers promising results to combat metabolic derangements in rodent models; however, it is not certain if these benefits can be translated to humans. Umbilical cord-derived mesenchymal stem cells (MSCs) are of fetal origin and are precursors to the satellite cell niche of SM in infants. Thus, MSCs can be used as an in vitro model for infant cellular metabolism. Closer insight into the programming of offspring metabolic tissue would allow for a better understanding of the benefit that maternal exercise has on offspring health and may provide a potential early target for combating metabolic disease risk. The purpose of this study will be to determine if the “Athlete’s Paradox” phenotype is retained in offspring of women who exercised during pregnancy. METHODS: Undifferentiated MSCs from women with obesity and gestational diabetes (GDM) will be cultured and compared to MSCs of women who are lean or exercised during pregnancy. At confluency, Oil Red O will be used to stain for lipid content. Radiolabeled glucose will be used to measure glycogen synthesis in the presence or absence of insulin as an index of insulin sensitivity. Insulin signaling proteins in the MSCs will also be measured in the basal and insulin-stimulated state. Results will be analyzed using unpaired t-tests, one-way or two-way repeated measures ANOVA, where appropriate. Factors tested will be group and treatment differences (i.e., insulin). ANTICIPATED RESULTS: We hypothesize that MSCs from women who exercised during pregnancy will retain the “Athlete’s Paradox” phenotype and display higher lipid content and higher insulin sensitivity compared to MSCs from women metabolically impaired (obesity and GDM) in pregnancy

Investigation of Glucose-phosphates in Skeletal Muscle Biopsies by 1H HR-MAS NMR: Comparison between Active and Sedentary Subjects

The aim of this 1H HR-MAS NMR study was to investigate biopsies of skeletal muscles comparing athletes, sedentary slim and sedentary obese subjects. 1H HR-MAS allows the direct assessment of glucose-phosphates contained in skeletal muscle biopsies, as was also previously shown. The current study is the first example for a potential application, demonstrating differences in glucose-phosphates between muscle tissues from athletes and sedentary subjects. The results suggest that quantitative assessment by 1H HR-MAS NMR of Glc-1P and Glc-6P being key players in energy metabolism may prove important for metabolic studies in biopsies

INVESTIGATION OF BLOOD LACTATE AS A MARKER OF METABOLIC DYSFUNCTION DURING PREGNANCY

Jill M. Maples1, Nicholas T. Broskey2, Maire Blankenship3, Alissa Paudel1, Alicia Mastronardi1, Nikki B. Zite1, Jaclyn B. van Nes1, Kimberly B. Fortner1, Rachel A. Tinius, FACSM3. 1University of Tennessee Graduate School of Medicine, Knoxville, TN. 2East Carolina University, Greenville, NC. 3Western Kentucky University, Bowling Green, KY. BACKGROUND: Previous work suggests blood lactate can be used as an indicator of metabolic disease and is a useful predictor of clinical outcomes in non-pregnant populations. However, the utility of lactate as an indicator of metabolic dysfunction during pregnancy is unknown. The purpose of this study is to determine if fasting or postprandial lactate is related to established markers of metabolic dysfunction (weight status, insulin resistance, substrate oxidation) during pregnancy. The ability to detect metabolic dysfunction during pregnancy has the potential to impact the immediate and future health of both mother and infant. METHODS: Lactate, glucose, and insulin values were assessed in 64 participants during late pregnancy (34.5±1.7 weeks gestation) before (fasting) and after a high-fat meal (1hr). Insulin and glucose levels were used to calculate HOMA-IR, which is an index of insulin resistance. Respiratory quotient (RQ), which reflects the relative contribution of fat and carbohydrate oxidation, was estimated using indirect calorimetry. Height (objectively assessed) and pre-pregnancy weight (self-reported) were used to estimate pre-pregnancy Body Mass Index (BMI). Means were compared and potential correlations were assessed using nonparametric tests. Partial correlations were used to adjust for potential confounders. RESULTS: Fasting and 1hr lactate were higher among those with pre-pregnancy overweight/obese (OWOB, n=29) compared to lean (n=35) (fasting: OWOB 0.90±0.26 v lean 0.72±0.26, p=0.007; 1hr: OWOB 1.01±0.37 v lean 0.76±0.28, p=0.005). Fasting and 1hr lactate values were positively correlated to fasting and 1hr insulin and HOMA-IR (p\u3c0.05). When adjusting for pre-pregnancy BMI, only 1hr lactate (not fasting) was correlated to insulin (1hr) and HOMA-IR (fasting and 1hr)(p\u3c0.05). Fasting and 1hr lactate was positively correlated to 1hr RQ and this remained when adjusting for pre-pregnancy BMI and HOMA-IR(p\u3c0.05). CONCLUSIONS: These data indicate lactate is associated with other markers of metabolic dysfunction during pregnancy. Future work should assess the clinical utility of lactate (fasting or postprandial), assessed at time points throughout pregnancy, as a potential biomarker for metabolic dysfunction or adverse obstetric outcomes, as in gestational or pre-pregnancy diabetes or fetal growth restriction. Funding was provided by NIH NIGMS Grant 5P20GM103436, WKU RCAP Grant 17-8011, and UTGSM Coffman Pediatric Research Endowment