title: Skeletal muscle hypertrophy adaptations predominate in the early stages of resistance exercise training, matching deuterium oxide-derived measures of muscle protein synthesis and mechanistic target of rapamycin complex 1 signaling.
abstract: Resistance exercise training (RET) is widely used to increase muscle mass in athletes and also aged/cachectic populations. However, the time course and metabolic and molecular control of hypertrophy remain poorly defined. Using newly developed deuterium oxide (D2O)-tracer techniques, we investigated the relationship between long-term muscle protein synthesis (MPS) and hypertrophic responses to RET. A total of 10 men (23 ± 1 yr) undertook 6 wk of unilateral (1-legged) RET [6 × 8 repetitions, 75% 1 repetition maximum (1-RM) 3/wk], rendering 1 leg untrained (UT) and the contralateral, trained (T). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom percentage; thereafter 50 ml/wk) with regular body water monitoring in saliva via high-temperature conversion elemental analyzer:isotope ratio mass spectrometer. Further bilateral VL muscle biopsies were taken at 3 and 6 wk to temporally quantify MPS via gas chromatography:pyrolysis:isotope ratio mass spectrometer. Expectedly, only the T leg exhibited marked increases in function [i.e., 1-RM/maximal voluntary contraction (60°)] and VL thickness (peaking at 3 wk). Critically, whereas MPS remained unchanged in the UT leg (e.g., ∼1.35 ± 0.08%/d), the T leg exhibited increased MPS at 0-3 wk (1.6 ± 0.01%/d), but not at 3-6 wk (1.29 ± 0.11%/d); this was reflected by dampened acute mechanistic target of rapamycin complex 1 signaling responses to RET, beyond 3 wk. Therefore, hypertrophic remodeling is most active during the early stages of RET, reflecting longer-term MPS. Moreover, D2O heralds promise for coupling MPS and muscle mass and providing insight into the control of hypertrophy and efficacy of anabolic interventions.
authors.affiliation: *Medical Research Council-Arthritis Research UK Centre of Excellence for Musculoskeletal Ageing Research, Division of Clinical, Metabolic, and Molecular Physiology, University of Nottingham, Derby, United Kingdom; and Department of Surgery, Royal Derby Hospital, Derby, United Kingdom.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Brook
authors.affiliation: *Medical Research Council-Arthritis Research UK Centre of Excellence for Musculoskeletal Ageing Research, Division of Clinical, Metabolic, and Molecular Physiology, University of Nottingham, Derby, United Kingdom; and Department of Surgery, Royal Derby Hospital, Derby, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilkinson
authors.affiliation: *Medical Research Council-Arthritis Research UK Centre of Excellence for Musculoskeletal Ageing Research, Division of Clinical, Metabolic, and Molecular Physiology, University of Nottingham, Derby, United Kingdom; and Department of Surgery, Royal Derby Hospital, Derby, United Kingdom.
authors.forename: William K
authors.initials: WK
authors.lastname: Mitchell
authors.affiliation: *Medical Research Council-Arthritis Research UK Centre of Excellence for Musculoskeletal Ageing Research, Division of Clinical, Metabolic, and Molecular Physiology, University of Nottingham, Derby, United Kingdom; and Department of Surgery, Royal Derby Hospital, Derby, United Kingdom.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Lund
authors.affiliation: *Medical Research Council-Arthritis Research UK Centre of Excellence for Musculoskeletal Ageing Research, Division of Clinical, Metabolic, and Molecular Physiology, University of Nottingham, Derby, United Kingdom; and Department of Surgery, Royal Derby Hospital, Derby, United Kingdom.
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Szewczyk
authors.affiliation: *Medical Research Council-Arthritis Research UK Centre of Excellence for Musculoskeletal Ageing Research, Division of Clinical, Metabolic, and Molecular Physiology, University of Nottingham, Derby, United Kingdom; and Department of Surgery, Royal Derby Hospital, Derby, United Kingdom.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
authors.affiliation: *Medical Research Council-Arthritis Research UK Centre of Excellence for Musculoskeletal Ageing Research, Division of Clinical, Metabolic, and Molecular Physiology, University of Nottingham, Derby, United Kingdom; and Department of Surgery, Royal Derby Hospital, Derby, United Kingdom.
authors.forename: Ken
authors.initials: K
authors.lastname: Smith
authors.affiliation: *Medical Research Council-Arthritis Research UK Centre of Excellence for Musculoskeletal Ageing Research, Division of Clinical, Metabolic, and Molecular Physiology, University of Nottingham, Derby, United Kingdom; and Department of Surgery, Royal Derby Hospital, Derby, United Kingdom philip.atherton@nottingham.ac.uk.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Atherton
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000328:Adult; D017666:Deuterium Oxide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015444:Exercise / Q000502:physiology*; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D017666:Deuterium Oxide
keywords: D20; anabolic signaling; stable isotopes