Synchronous deficits in cumulative muscle protein synthesis and ribosomal biogenesis underlie age‐related anabolic resistance to exercise in humans

Abstract

Key points Resistance exercise training (RET) is one of the most effective strategies for preventing declines in skeletal muscle mass and strength with age.Hypertrophic responses to RET with age are diminished compared to younger individuals.In response to 6 weeks RET, we found blunted hypertrophic responses with age are underpinned by chronic deficits in long‐term muscle protein synthesis.We show this is likely to be the result of multifactorial deficits in anabolic hormones and blunted translational efficiency and capacity.These results provide great insight into age‐related exercise adaptations and provide a platform on which to devise appropriate nutritional and exercise interventions on a longer term basis. AbstractAgeing is associated with impaired hypertrophic responses to resistance exercise training (RET). Here we investigated the aetiology of ‘anabolic resistance’ in older humans. Twenty healthy male individuals, 10 younger (Y; 23 ± 1 years) and 10 older (O; 69 ± 3 years), performed 6 weeks unilateral RET (6 × 8 repetitions, 75% of one repetition maximum (1‐RM), 3 times per week). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom%; thereafter 50 ml week−1), further bilateral VL muscle biopsies were taken at 3 and 6 weeks to quantify muscle protein synthesis (MPS) via gas chromatography–pyrolysis–isotope ratio mass spectrometry. After RET, 1‐RM increased in Y (+35 ± 4%) and O (+25 ± 3%; P < 0.01), while MVC increased in Y (+21 ± 5%; P < 0.01) but not O (+6 ± 3%; not significant (NS)). In comparison to Y, O displayed blunted RET‐induced increases in muscle thickness (at 3 and 6 weeks, respectively, Y: +8 ± 1% and +11 ± 2%, P < 0.01; O: +2.6 ± 1% and +3.5 ± 2%, NS). While ‘basal’ longer term MPS was identical between Y and O (∼1.35 ± 0.1% day−1), MPS increased in response to RET only in Y (3 weeks, Y: 1.61 ± 0.1% day−1; O: 1.49 ± 0.1% day−1). Consistent with this, O exhibited inferior ribosomal biogenesis (RNA:DNA ratio and c‐MYC induction: Y: +4 ± 2 fold change; O: +1.9 ± 1 fold change), translational efficiency (S6K1 phosphorylation, Y: +10 ± 4 fold change; O: +4 ± 2 fold change) and anabolic hormone milieu (testosterone, Y: 367 ± 19; O: 274 ± 19 ng dl−1 (all P < 0.05). Anabolic resistance is thus multifactorial.

Exercise training response heterogeneity: physiological and molecular insights

“…Ageing is associated with impaired hypertrophic responses to resistance exercise training (anabolic resistance) [10][11][12][13][14]. However, equal adaptations to high-intensity aerobic training in insulin sensitivity, V O 2peak and skeletal muscle mitochondrial respiration have been reported in older and younger individuals [15], and chronically trained older individuals have high mitochondrial content, function and exercise efficiencies [16].…”

Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise

“…Leg absolute synthetic rate (ASR) and absolute breakdown rate (ABR) were calculated as previously described (20). In brief, ;15 mg of frozen muscle tissue was freeze dried and weighed, then homogenized in 0.2 M perchloric acid (PCA) and spun to form a pellet.…”

Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy

“…The well-known blunted capacity for RT-induced myofiber hypertrophy with advancing age is associated with blunted induction of key regulatory processes: (1) In response to a single bout of resistance exercise, expression of 45S pre-rRNA was up-regulated in adults 39 years of age but not in 76-year-olds (Stec et al 2015); (2) during 6 weeks of RT, surrogate indices of ribosome biogenesis (RNA:DNA-ratio and c-Myc induction) were impaired in conjunction with blunted muscle hypertrophy in old versus young adults (Brook et al 2016); and (3) using the synergist ablation model, the blunted hypertrophy noted in aged mice was linked to blunted ribosome biogenesis as indicated by impaired induction of both pre-rRNA and rRNA (Kirby et al 2015). Further, it was recently noted that muscle expression levels of 45S pre-rRNA and c-myc increase substantially after an acute resistance exercise bout in untrained subjects (Nader et al 2014), although these responses are blunted in the trained state.…”