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• W2593179916 abstract "•High-intensity interval training improved age-related decline in muscle mitochondria•Training adaptations occurred with increased gene transcripts and ribosome proteins•Changes to RNA with training had little overlap with corresponding protein abundance•Enhanced ribosomal abundance and protein synthesis explain gains in mitochondria The molecular transducers of benefits from different exercise modalities remain incompletely defined. Here we report that 12 weeks of high-intensity aerobic interval (HIIT), resistance (RT), and combined exercise training enhanced insulin sensitivity and lean mass, but only HIIT and combined training improved aerobic capacity and skeletal muscle mitochondrial respiration. HIIT revealed a more robust increase in gene transcripts than other exercise modalities, particularly in older adults, although little overlap with corresponding individual protein abundance was noted. HIIT reversed many age-related differences in the proteome, particularly of mitochondrial proteins in concert with increased mitochondrial protein synthesis. Both RT and HIIT enhanced proteins involved in translational machinery irrespective of age. Only small changes of methylation of DNA promoter regions were observed. We provide evidence for predominant exercise regulation at the translational level, enhancing translational capacity and proteome abundance to explain phenotypic gains in muscle mitochondrial function and hypertrophy in all ages. The molecular transducers of benefits from different exercise modalities remain incompletely defined. Here we report that 12 weeks of high-intensity aerobic interval (HIIT), resistance (RT), and combined exercise training enhanced insulin sensitivity and lean mass, but only HIIT and combined training improved aerobic capacity and skeletal muscle mitochondrial respiration. HIIT revealed a more robust increase in gene transcripts than other exercise modalities, particularly in older adults, although little overlap with corresponding individual protein abundance was noted. HIIT reversed many age-related differences in the proteome, particularly of mitochondrial proteins in concert with increased mitochondrial protein synthesis. Both RT and HIIT enhanced proteins involved in translational machinery irrespective of age. Only small changes of methylation of DNA promoter regions were observed. We provide evidence for predominant exercise regulation at the translational level, enhancing translational capacity and proteome abundance to explain phenotypic gains in muscle mitochondrial function and hypertrophy in all ages. Health benefits of exercise are indisputable in combating age-related risks for disease and disability (Myers et al., 2002Myers J. Prakash M. Froelicher V. Do D. Partington S. Atwood J.E. Exercise capacity and mortality among men referred for exercise testing.N. Engl. J. Med. 2002; 346: 793-801Crossref PubMed Scopus (2865) Google Scholar), and understanding the transducers of such benefits is of high national interest (Neufer et al., 2015Neufer P.D. Bamman M.M. Muoio D.M. Bouchard C. Cooper D.M. Goodpaster B.H. Booth F.W. Kohrt W.M. Gerszten R.E. Mattson M.P. et al.Understanding the cellular and molecular mechanisms of physical activity-induced health benefits.Cell Metab. 2015; 22: 4-11Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar). Aerobic exercise training leads to skeletal muscle protein remodeling and stimulates multiple molecular steps,including DNA methylation (Barrès et al., 2012Barrès R. Yan J. Egan B. Treebak J.T. Rasmussen M. Fritz T. Caidahl K. Krook A. O’Gorman D.J. Zierath J.R. Acute exercise remodels promoter methylation in human skeletal muscle.Cell Metab. 2012; 15: 405-411Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar) and synthesis of new proteins (Short et al., 2003Short K.R. Vittone J.L. Bigelow M.L. Proctor D.N. Rizza R.A. Coenen-Schimke J.M. Nair K.S. Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity.Diabetes. 2003; 52: 1888-1896Crossref PubMed Scopus (490) Google Scholar). Many studies have demonstrated changes to mRNA content, but the extent to which transcriptional changes lead to changes in protein abundance remains inconclusive (Miller et al., 2016Miller B.F. Konopka A.R. Hamilton K.L. The rigorous study of exercise adaptations: why mRNA might not be enough.J. Appl. Physiol. 2016; 121: 594-596Crossref PubMed Scopus (39) Google Scholar). Understanding the regulation of skeletal muscle molecular adaptations to diverse types of exercise training can help to develop future targeted therapies and exercise recommendations. There is a gap in knowledge about age effects on pathways regulating exercise adaptations in response to different exercise modalities. Different types of exercise can stimulate variable, but specific, responses in muscle functions. Aerobic exercise training enhances mitochondrial oxidative enzymes’ capacity (Holloszy, 1967Holloszy J.O. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle.J. Biol. Chem. 1967; 242: 2278-2282Abstract Full Text PDF PubMed Google Scholar) and coincides with improvements to insulin sensitivity with age (Lanza et al., 2008Lanza I.R. Short D.K. Short K.R. Raghavakaimal S. Basu R. Joyner M.J. McConnell J.P. Nair K.S. Endurance exercise as a countermeasure for aging.Diabetes. 2008; 57: 2933-2942Crossref PubMed Scopus (410) Google Scholar). It remains to be determined whether age-related decline in muscle mitochondrial protein synthesis (Rooyackers et al., 1996Rooyackers O.E. Adey D.B. Ades P.A. Nair K.S. Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle.Proc. Natl. Acad. Sci. USA. 1996; 93: 15364-15369Crossref PubMed Scopus (466) Google Scholar) is reversed by aerobic training. High-intensity aerobic interval training (HIIT) involves repeating short bouts of activity at near-maximal intensity, which rapidly and robustly increases aerobic capacity, mitochondrial respiration, and insulin sensitivity in young people (Burgomaster et al., 2008Burgomaster K.A. Howarth K.R. Phillips S.M. Rakobowchuk M. Macdonald M.J. McGee S.L. Gibala M.J. Similar metabolic adaptations during exercise after low volume sprint interval and traditional endurance training in humans.J. Physiol. 2008; 586: 151-160Crossref PubMed Scopus (832) Google Scholar, Irving et al., 2011Irving B.A. Short K.R. Nair K.S. Stump C.S. Nine days of intensive exercise training improves mitochondrial function but not insulin action in adult offspring of mothers with type 2 diabetes.J. Clin. Endocrinol. Metab. 2011; 96: E1137-E1141Crossref PubMed Scopus (37) Google Scholar). Resistance training (RT) reverses sarcopenia and age-related declines in myosin heavy-chain gene transcripts and synthesis rates of muscle proteins (Balagopal et al., 2001Balagopal P. Schimke J.C. Ades P. Adey D. Nair K.S. Age effect on transcript levels and synthesis rate of muscle MHC and response to resistance exercise.Am. J. Physiol. Endocrinol. Metab. 2001; 280: E203-E208Crossref PubMed Google Scholar), but a comprehensive gene transcripts and proteome comparison with aerobic training has not been performed. Combined training (CT) offers many benefits of both aerobic and resistance training, although the intensity of aerobic and resistance components are lower than either HIIT or standard RT programs (Irving et al., 2015Irving B.A. Lanza I.R. Henderson G.C. Rao R.R. Spiegelman B.M. Nair K.S. Combined training enhances skeletal muscle mitochondrial oxidative capacity independent of age.J. Clin. Endocrinol. Metab. 2015; 100: 1654-1663Crossref PubMed Scopus (72) Google Scholar). Lower exercise intensity may limit training adaptations (Ross et al., 2015Ross R. de Lannoy L. Stotz P.J. Separate effects of intensity and amount of exercise on interindividual cardiorespiratory fitness response.Mayo Clin. Proc. 2015; 90: 1506-1514Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar), particularly of mitochondria (MacInnis et al., 2016MacInnis M.J. Zacharewicz E. Martin B.J. Haikalis M.E. Skelly L.E. Tarnopolsky M.A. Murphy R.M. Gibala M.J. Superior mitochondrial adaptations in human skeletal muscle after interval compared to continuous single-leg cycling matched for total work.J. Physiol. 2016; (Published online July 11, 2016)https://doi.org/10.1113/JP272570Crossref Scopus (121) Google Scholar). A comprehensive approach to different exercise programs and the specific physiological and molecular adaptations and the potential impact of age on these adaptations remain to be determined. We performed comprehensive metabolic and molecular phenotyping of young and older adults in response to 12 weeks of aerobic training (using HIIT), RT, and 12 weeks of a sedentary period followed by CT of moderate-intensity aerobic plus resistance training. These measurements were performed 72 hr following the last bout of exercise to specifically determine the training effect. We hypothesized that skeletal muscle transcriptome, translation, and proteome would increase with training, and the pattern of responses would reflect the type of training modality and phenotype changes. HIIT robustly improved cardio-respiratory fitness, insulin sensitivity, mitochondrial respiration, and fat-free mass (FFM) in both age groups. RT improved FFM and insulin sensitivity in both age groups while CT had lesser gains, perhaps due to differences in training intensity. RNA sequencing of muscle biopsies revealed robust increases in mRNA expression with HIIT, more so than RT or CT, particularly of mitochondrial transcripts. Quantitative proteomics in response to HIIT revealed larger proteomic changes, particularly in mitochondrial and ribosome proteins, as well as reversal of many age-related changes. We report relatively small changes (<10%) to methylation of DNA promoter regions and low overlap between transcriptional and proteomic changes. Thus, our findings indicate that the regulation of exercise adaptation is tightly linked with protein translation and translational machinery. The prospective exercise training study (Figure 1) was approved by the Mayo Clinic Institutional Review Board, registered at https://clinicaltrials.gov (#NCT01477164) and conducted in accordance with the Declaration of Helsinki. All participants provided informed written consent. Participants were recruited into two distinct age groups: young (18–30 years) or older (65–80 years) with a goal of an equal number of men and women. The final groups were approximately balanced for sex, and all women in the older group were post-menopausal. Exclusion criteria were structured regular exercise (>20 min, twice weekly), cardiovascular disease, metabolic diseases (type 2 diabetes mellitus, fasting blood glucose > 110 mg/dL, and untreated hypothyroidism or hyperthyroidism), renal disease, high body mass index (BMI > 32 kg/m2), implanted metal devices, pregnancy, smoking, and history of blood clotting disorders. Exclusionary medication included anticoagulants, insulin, insulin sensitizers, corticosteroids, sulfonylureas, barbiturates, peroxisome proliferator-activated receptor γ agonists, β blockers, opiates, and tricyclic antidepressants. Following baseline measurements, the participants were randomized to three groups (HIIT, RT, or CT) using gRand (v1.1, Peter A. Charpentier) following a permuted block strategy with block length of 15 and 2 factors (age and sex). HIIT was 3 days per week of cycling (4 × 4 min at >90% of peak oxygen consumption [VO2 peak] with 3 min pedaling at no load) and 2 days per week of treadmill walking (45 min at 70% of VO2 peak). RT consisted of lower and upper body exercises (4 sets of 8–12 repetitions) 2 days each per week. CT participants first underwent a 12-week sedentary period (SED) and wore accelerometers to record any structured activity. Following SED, participants underwent metabolic studies and began CT of 5 days per week cycling (30 min at 70% VO2 peak) and 4 days per week weight lifting with fewer repetitions than RT. Both baseline and post-training studies were performed in all participants. Baseline subject characteristics show that older participants had higher body fat percentage, BMI, and fasting plasma glucose concentrations despite similar fasting insulin concentrations (Table 1). During training, the weekly energy expenditure of exercise in kcal per FFM was highest with HIIT (Young: 26 ± 3; Older: 18.5 ± 2, p < 0.001) followed by CT (Young: 22.8 ± 2; Older 16.9 ± 1, p < 0.05) and lowest with RT (Young: 9.6 ± 2; Older 7.3 ± 1, p < 0.0001). All baseline comparisons are mean ± SD.Table 1Baseline Differences between Young and Older ParticipantsYoungOlderANOVA p valueHIITResistanceCombinedHIITResistanceCombinedAgeGroupAge × GroupN14 (7 M/7 F)11 (5 M/6 F)9 (5 M/4 F)9 (4 M/5 F)9 (5 M/4 F)8 (5 M/3 F)N/AN/AN/AAge25.4 y (4.3 y)23.7 y (3.5 y)26.3 y (2.7 y)70.7 y (4.6 y)70.3 y (3.9 y)68.6 y (3.4 y)N/AN/AN/AHeight174.5 cm (6.9 cm)172.3 cm (14 cm)173.4 cm (8.7 cm)170.7 cm (10.7 cm)168.9 cm (10.8 cm)169.5 cm (9.7 cm)0.14580.87450.9987Weight75 kg (9.7 kg)73.8 kg (14.3 kg)77.9 kg (17.1 kg)80.3 kg (17 kg)76.4 kg (13.7 kg)77 kg (16 kg)0.55340.84750.8041BMI24.6 kg/m2 (2.3 kg/m2)24.7 kg/m2 (2.7 kg/m2)25.6 kg/m2 (3.3 kg/m2)27.3 kg/m2 (3.3 kg/m2)26.6 kg/m2 (2 kg/m2)26.6 kg/m2 (3.8 kg/m2)0.01380.83770.6606Body Fat33.5% (7.1%)28.3% (8.9%)31.9% (4.7%)36.2% (4.6%)38.5% (4.5%)37.9% (6.1%)0.00020.55530.1088Fasting Insulin5.6 μIU/mL (2 μIU/mL)5.7 μIU/mL (3.8 μIU/mL)5.5 μIU/mL (2.6 μIU/mL)5 μIU/mL (3.1 μIU/mL)5.8 μIU/mL (2.1 μIU/mL)4.3 μIU/mL (1.8 μIU/mL)0.56980.81850.4807Fasting Glucose97 mg/dL (4 mg/dL)96 mg/dL (6 mg/dL)96 mg/dL (7 mg/dL)104 mg/dL (11 mg/dL)103 mg/dL (10 mg/dL)105 mg/dL (8 mg/dL)0.00030.64460.9092Body composition was measured by dual energy X-ray absorptiometry. Data are mean with SD. BMI, body mass index; FFM, fat-free mass; HIIT, high-intensity interval training; N/A, not applicable. Open table in a new tab Body composition was measured by dual energy X-ray absorptiometry. Data are mean with SD. BMI, body mass index; FFM, fat-free mass; HIIT, high-intensity interval training; N/A, not applicable. VO2 peak during a graded exercise test was determined at baseline and following training. There was a high correlation (r2 = 0.988, p < 0.0001) and low variability between pre- and post-SED VO2 peak even though measurements were separated by 12 weeks (Young: Pre = 2,643 ± 649, Post = 2,517 ± 603; Old: Pre = 1,646 ± 567, Post = 1,627 ± 550 mL/min, Figure S7). The respiratory exchange ratio (RER) for SED group was also consistent for both young (Pre: 1.2 ± 0.1, Post: 1.2 ± 0.1) and older adults (Pre: 1.2 ± 0.1, Post: 1.2 ± 0.1), indicating that VO2 peak measurements were done during identical conditions. Compared to young, older adults had ∼30% lower VO2 peak relative to body weight (Figure 2A). Absolute VO2 peak (mL/min) significantly increased in the younger group following HIIT (mean[95%CI]: +637[462–812] p < 0.0001) with lesser but significant increase with RT (+185[1–368] p = 0.048) and CT (+429[223–634] p = 0.0001). In the older group, absolute VO2 peak also increased following HIIT (278[72–483] p = 0.0091) and CT (+295[75–514] p = 0.0096); however, the increase in absolute VO2 peak of the older RT group did not reach statistical significance (+203[−3–409] p = 0.053). In the young group, HIIT produced the highest increase of ∼28% in relative VO2 peak (+8.3[6.2–10.3] p < 0.0001 mL/kgBW/min) followed by ∼17% with CT (+5.3[2.9–7.6] p < 0.0001) (Figure 2B) without any significant increase with RT. In the older group, relative VO2 peak increased ∼17% with HIIT (+3.5[1.2–5.9] p = 0.0042) and ∼21% with CT (+4.4[1.8–6.9] p = 0.0011) without any significant change following RT (+2.3[−0.1–4.6] p = 0.06) (Figure 2B). Frailty with age is largely due to muscle wasting and weakness or sarcopenia (Goodpaster et al., 2006Goodpaster B.H. Park S.W. Harris T.B. Kritchevsky S.B. Nevitt M. Schwartz A.V. Simonsick E.M. Tylavsky F.A. Visser M. Newman A.B. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study.J. Gerontol. A Biol. Sci. Med. Sci. 2006; 61: 1059-1064Crossref PubMed Scopus (1877) Google Scholar). Declines in FFM and muscle quality (e.g., force per muscle mass) with age contribute to decreased exercise capacity (Delmonico et al., 2009Delmonico M.J. Harris T.B. Visser M. Park S.W. Conroy M.B. Velasquez-Mieyer P. Boudreau R. Manini T.M. Nevitt M. Newman A.B. Goodpaster B.H. Health, Aging, and BodyLongitudinal study of muscle strength, quality, and adipose tissue infiltration.Am. J. Clin. Nutr. 2009; 90: 1579-1585Crossref PubMed Scopus (884) Google Scholar). We investigated the response of muscle mass and quality to different exercise modalities. Baseline whole-body FFM was similar between young and older groups (Figure 2C). Whole-body FFM increased in all training groups, with the greatest increase in young RT (2.2 kg; +4%, p < 0.0001; Figure 2D). Leg strength was lower in older humans in absolute terms or relative to leg FFM (Figure 2E, Young: 15.8 ± 3.8, Older: 13 ± 4.1 one-repetition maximum [1RM]/kg leg FFM, p = 0.017), suggesting lower muscle quality with age. The training groups with resistance training (RT and CT) had increased leg strength per change in leg mass, indicating an increase in the capacity for a given mass of muscle to produce force (Figure 2F). Leg strength did not change significantly with HIIT, possibly due to training specificity associated with cycling versus leg press exercises. Alternatively, the increase in strength was related to increase in muscle mass. These results demonstrate that both muscle strength and mass robustly improved with CT and RT in both younger and older adults. Collectively, the gains in whole-body FFM suggest that a high-intensity aerobic stimulus can induce both aerobic and hypertrophy adaptations. Exercise intensity is a strong influence on adaptations. CT had lower-intensity aerobic and resistance components than HIIT and RT, respectively. Approaches to improve exercise responses will have positive benefits on public health, and raising exercise intensity can increase the number of exercise responders (Ross et al., 2015Ross R. de Lannoy L. Stotz P.J. Separate effects of intensity and amount of exercise on interindividual cardiorespiratory fitness response.Mayo Clin. Proc. 2015; 90: 1506-1514Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). A previous work in younger adults demonstrated that 12 weeks of HIIT increased VO2 peak and muscle citrate synthase activity to a similar extent as longer duration of lower-intensity aerobic exercise training (Gillen et al., 2016Gillen J.B. Martin B.J. MacInnis M.J. Skelly L.E. Tarnopolsky M.A. Gibala M.J. Twelve weeks of sprint interval training improves indices of cardiometabolic health similar to traditional endurance training despite a five-fold lower exercise volume and time commitment.PLoS ONE. 2016; 11: e0154075Crossref PubMed Scopus (198) Google Scholar). We demonstrate that HIIT is a feasible approach to increase exercise intensity in healthy younger and older adults. Younger adults demonstrated more robust increase of VO2 peak in response to HIIT unlike older adults who responded equally to HIIT and CT (Figure 2B). Older adults are at risk for developing insulin resistance associated with sedentary lifestyle and gains in adiposity (Karakelides et al., 2010Karakelides H. Irving B.A. Short K.R. O’Brien P. Nair K.S. Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function.Diabetes. 2010; 59: 89-97Crossref PubMed Scopus (186) Google Scholar). Exercise can improve insulin sensitivity, and we sought to clearly define the age effect on different types of exercise training and age on insulin sensitivity. For this, we measured peripheral insulin sensitivity as the glucose rate of disappearance (Rd [glucose rate of disappearance] μmol/kgFFM/min) during a two-stage hyperinsulinemic-euglycemic clamp (mean ± SD steady state glucose was 88 ± 6 mg/dL) at baseline and after exercise training in all groups (Figures S1 and S3). At baseline, young and older adults had similar insulin sensitivity (Figure 2G). Rd increased in all training groups, except in older CT (Figure 2H). Fasting insulin and glucose did not change with training in either age group (Figure S1). Predominant fates of glucose in skeletal muscle are either oxidative as fuel or non-oxidative for storage as glycogen. Non-oxidative glucose disposal increased with training (Figure S3), indicating greater storage rather than oxidation, which is a useful training adaptation for promoting exercise performance. These results are consistent with a previous cross-sectional study showing chronically trained older and younger adults have similar measurements of insulin sensitivity (Lanza et al., 2008Lanza I.R. Short D.K. Short K.R. Raghavakaimal S. Basu R. Joyner M.J. McConnell J.P. Nair K.S. Endurance exercise as a countermeasure for aging.Diabetes. 2008; 57: 2933-2942Crossref PubMed Scopus (410) Google Scholar). We did not detect any changes to hepatic insulin sensitivity (Figures S2 and S3), indicating that improvements were predominantly in skeletal muscle metabolism, suggesting that the previous cross-sectional data showing enhanced insulin sensitivity to endogenous glucose production represent long-term (≥4 years) exercise training effect (Lanza et al., 2008Lanza I.R. Short D.K. Short K.R. Raghavakaimal S. Basu R. Joyner M.J. McConnell J.P. Nair K.S. Endurance exercise as a countermeasure for aging.Diabetes. 2008; 57: 2933-2942Crossref PubMed Scopus (410) Google Scholar). A major exercise effect to skeletal muscle metabolism is mitochondrial oxidative capacity. Declines in mitochondrial content with age are closely linked to reduced cardiorespiratory fitness (Short et al., 2005Short K.R. Bigelow M.L. Kahl J. Singh R. Coenen-Schimke J. Raghavakaimal S. Nair K.S. Decline in skeletal muscle mitochondrial function with aging in humans.Proc. Natl. Acad. Sci. USA. 2005; 102: 5618-5623Crossref PubMed Scopus (857) Google Scholar). Decreased resting mitochondrial ATP production has been implicated in the development of insulin resistance with aging (Petersen et al., 2003Petersen K.F. Befroy D. Dufour S. Dziura J. Ariyan C. Rothman D.L. DiPietro L. Cline G.W. Shulman G.I. Mitochondrial dysfunction in the elderly: possible role in insulin resistance.Science. 2003; 300: 1140-1142Crossref PubMed Scopus (1683) Google Scholar). Indeed, a relationship between insulin-resistant states and decreased oxidative enzymes in skeletal muscle has been previously reported in obesity and type 2 diabetes (Simoneau and Kelley, 1997Simoneau J.A. Kelley D.E. Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM.J. Appl. Physiol. 1997; 83: 166-171Crossref PubMed Scopus (351) Google Scholar). However, this relationship is not always observed (Karakelides et al., 2010Karakelides H. Irving B.A. Short K.R. O’Brien P. Nair K.S. Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function.Diabetes. 2010; 59: 89-97Crossref PubMed Scopus (186) Google Scholar). We investigated aging and exercise training effects on isolated mitochondria from skeletal muscle biopsy samples collected in the resting and fasting state and then determined maximal mitochondrial oxygen consumption by high-resolution respirometry. At baseline, maximal respiration was lower in older adults compared to young for the respiratory complexes (Complex I+II displayed in Figures 3A and 3C ), expressed in either absolute units or normalized to mitochondrial protein content. HIIT increased maximal absolute mitochondrial respiration in young (+49%) and older adults (+69%), whereas a significant increase following CT was observed in young (+38%), but not older adults (Figures 3B and 3D). RT did not increase mitochondrial respiration significantly in either age group. The intrinsic functions of mitochondria, including coupling efficiency and reactive oxygen species production, were not different either between age groups or in response to training (Figures S4A–S4D). Older adults had lower mtDNA copy number when normalized to nDNA, consistent with a decline in mitochondria content with age (Figure S4E). HIIT and RT increased mtDNA content in older adults, with non-significant gains following CT (Figure S4F). Collectively, the mitochondrial data in our cohort of sedentary, but otherwise healthy, adults indicate that a change in mitochondrial protein content was a predominate contributor to the loss of mitochondrial respiratory capacity with age and gains with training. There was no difference in insulin sensitivity at baseline despite differences in mitochondrial respiration. These results are in agreement with our previous work showing that differences in insulin sensitivity are more related to changes in exercise status and adiposity rather than mitochondrial capacity (Karakelides et al., 2010Karakelides H. Irving B.A. Short K.R. O’Brien P. Nair K.S. Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function.Diabetes. 2010; 59: 89-97Crossref PubMed Scopus (186) Google Scholar). Insulin resistance is associated with decreased mitochondrial respiratory chain efficiency and increased reactive oxygen species (ROS) production (Anderson et al., 2009Anderson E.J. Lustig M.E. Boyle K.E. Woodlief T.L. Kane D.A. Lin C.T. Price 3rd, J.W. Kang L. Rabinovitch P.S. Szeto H.H. et al.Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans.J. Clin. Invest. 2009; 119: 573-581Crossref PubMed Scopus (946) Google Scholar), which can be restored in insulin-resistant women by aerobic training to those of a lean phenotype (Konopka et al., 2015Konopka A.R. Asante A. Lanza I.R. Robinson M.M. Johnson M.L. Dalla Man C. Cobelli C. Amols M.H. Irving B.A. Nair K.S. Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training.Diabetes. 2015; 64: 2104-2115Crossref PubMed Scopus (80) Google Scholar). Our current study of healthy older adults with insulin sensitivity similar to younger adults showed no difference in respiratory chain efficiency or ROS production despite lower mitochondrial capacity than the younger group, supporting a notion that reduced insulin sensitivity is not associated with reduced mitochondrial coupling efficiency. We investigated the extent to which changes in mRNA coincided with phenotypes to further understand the regulation of skeletal muscle changes with age and adaptations to exercise. We performed RNA sequencing on baseline and post-exercise training skeletal muscle biopsies to assess whether transcript levels account for aging or training phenotypes of mitochondria, muscle hypertrophy, and insulin sensitivity. At baseline, when compared to young, 267 gene transcripts were lower and 166 were higher in older people (Figure S5A). Several mitochondrial-, insulin signaling-, and muscle growth-related genes were downregulated with age (Figure S5A). In contrast, among all training regimens, HIIT increased the expression of the largest number of genes in both young and older, especially in mitochondrial, muscle growth, and insulin signaling pathways in older adults (Figures 4A and 4B ). In the older, HIIT increased 22 mitochondrial genes, including those involved with translational regulation (ribosomes MT-RNR1 and 2) and mitochondrial tRNA transferase for methionine (MT-TG), leucine (MT-TL1), valine (MT-TV), glycine (MT-TG), and arginine (MT-TR). When compared to HIIT, RT increased 35% and 70% fewer genes in young and old, respectively (Figures 4C and 4D), and CT increased 28% and 84% fewer genes in young and old, respectively (Figures 4E and 4F). These data demonstrate a varied response of gene transcripts based on exercise mode between young and older adults, and the greatest increase was following HIIT in older adults. Next, we determined whether training-induced gene sets are specific to training modes in young and older adults. The young had 274, 74, and 170 genes uniquely increased by HIIT, RT, and CT, respectively (Figure 4G). The older had 396, 33, and 19 genes uniquely increased by HIIT, RT, and CT, respectively (Figure 4H). Taken together, these data show that HIIT induced the largest gene expression change regardless of age. In older adults, the changes in gene expression with HIIT completely subsumes CT and RT changes. Given that older HIIT produced the largest gene expression change, we assessed whether these genes were unique or overlapping with the younger training groups. One-third of the older HIIT genes (181 out of 553) were also shared by the young HIIT group, and 114 of these were shared with young RT and CT groups (Figure 4I). Another third of older HIIT genes were unique to that group (186 out of 553; Figure 4I). Taken together, these data suggest that a large portion of older HIIT genes is age specific. HIIT had a robust effect on increasing gene transcript content, and we next considered whether training in older individuals reversed age-related loss of muscle gene transcripts, potentially contributing to changes in metabolic phenotypes. To test this, we rank ordered young versus old baseline gene transcript changes from most upregulated to most downregulated with age. A gene set enrichment analysis (GSEA) was performed using genes that were upregulated with either old HIIT (Figure 4J) or young HIIT (Figure S5B). We observed that a majority of genes that were upregulated with HIIT" @default.
• W2593179916 created "2017-03-16" @default.
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• W2593179916 title "Enhanced Protein Translation Underlies Improved Metabolic and Physical Adaptations to Different Exercise Training Modes in Young and Old Humans" @default.
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