title: Synchronous deficits in cumulative muscle protein synthesis and ribosomal biogenesis underlie age-related anabolic resistance to exercise in humans.
abstract: 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.
  
  
  
  Ageing 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.
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Brook
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilkinson
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.|Departments of Surgery, Royal Derby Hospital, Derby, UK.
authors.forename: William K
authors.initials: WK
authors.lastname: Mitchell
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.|Departments of Surgery, Royal Derby Hospital, Derby, UK.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Lund
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Phillips
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.
authors.forename: Nathaniel J
authors.identifier: 0000-0003-4425-9746
authors.initials: NJ
authors.lastname: Szewczyk
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Smith
authors.affiliation: MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology, University of Nottingham, Derby, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Atherton
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D014176:Protein Biosynthesis; D052097:Quadriceps Muscle / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000378:metabolism; D055070:Resistance Training; D012270:Ribosomes / Q000378:metabolism*; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; D012313:RNA; D004247:DNA
keywords: ageing; exercise; hypertrophy; muscle; protein synthesis; ribosomal biogenesis; signalling; stable isotope