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.

Abstract: 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 D₂ O (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.

Keywords: ageing; exercise; hypertrophy; muscle; protein synthesis; ribosomal biogenesis; signalling; stable isotope.

Figure 1

Schematic diagram of study protocol

Figure 2. Muscle strength, mass and architecture

Time course of changes in T legs as percentage change in 1‐RM from baseline (A), average percentage MVC from baseline (B), thigh fat free mass 0–6 weeks (C), VL MT (D), L _f (E) and θ (F). Values are means ± SEM. ^aSignificantly different from baseline, P < 0.05; ^bsignificantly different from previous time point, P < 0.05; ^csignificantly different from old, P < 0.05. 1‐RM, one repetition maximum; L _f, fibre length; MT, muscle thickness; T, trained; VL, vastus lateralis; θ, pennation angle.

Figure 3. Muscle protein, RNA and DNA concentrations

Time course of the changes in μg (mg dry weight muscle)⁻¹: ASP (A), RNA (B) and DNA (C); and ratios of ASP:DNA (D), RNA:DNA (E) and RNA:ASP (F). Values are means ± SEM. Significantly different from baseline: ^* P < 0.05, ^** P < 0.01; significantly different from old: ^§ P < 0.05. ASP, alkali soluble protein.

Figure 4. Muscle protein synthesis, absolute synthetic rate, fractional growth rate and absolute breakdown rate

A, muscle protein synthesis (MPS) rates in UT and T legs in Y and O individuals. B, fractional growth rate (FGR). C, absolute synthetic rate (ASR). D, absolute breakdown rate (ABR). Values are means ± SEM. ^*Significantly different from UT, P < 0.05. T, trained; UT, untrained.

Figure 5. Intramuscular signalling

Relative change compared with UT in mTORc1^Ser2448 (A), p70S6K1^Thr389 (B), rps6^ser240/244 (C), ERK1/2^Thr202Tyr204 (D), eEF2^Thr56 (E), Akt^Ser473 (F), 4EBP1^Thr37/46 (G), AMPK^Thr172 (H), Beclin‐1 (I), Cathepsin L (J), calpain 1 (K), MuRF1 (L), c‐MYC (M), pRB^Ser780 (N), TIF1a (O), UBF1^Ser484 (P), UBF1 (Q), TIF1a^Ser649 (R). Values are means ± SEM. ^*Significantly different from UT, P < 0.05. UT, untrained.

Figure 6. Correlations

Correlations between RNA:DNA at 3 weeks and MT at 3 weeks (A), RNA:DNA at 6 weeks and TFFM at 6 weeks (B), the increase in P70S6K1^T389 after first RET bout and the percentage change in MT at 3 weeks (C), the increase in P70S6K1^T389 after first RET bout and the percentage change in TFFM at 6 weeks (D), testosterone after first RET bout and the percentage change in MT at 3 weeks (E), percentage change in testosterone after first RET bout and the percentage change in TFFM at 6 weeks (F), protein intake (g (kg FFM)⁻¹ day⁻¹) and percentage change in MT at 3 weeks (G), and protein intake (g (kg FFM)⁻¹ day⁻¹) and percentage change in TFFM at 6 weeks (H). MT, muscle thickness; RET, resistance exercise trained; TFFM, thigh fat free mass.