Enhanced Protein Translation Underlies Improved Metabolic and Physical Adaptations to Different Exercise Training Modes in Young and Old Humans

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 prospective exercise training study 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.