Randomized, four-arm, dose-response clinical trial to optimize resistance exercise training for older adults with age-related muscle atrophy

Abstract

Purpose: The myriad consequences of age-related muscle atrophy include reduced muscular strength, power, and mobility; increased risk of falls, disability, and metabolic disease; and compromised immune function. At its root, aging muscle atrophy results from a loss of myofibers and atrophy of the remaining type II myofibers. The purpose of this trial (NCT02442479) was to titrate the dose of resistance training (RT) in older adults in an effort to maximize muscle regrowth and gains in muscle function.

Methods: A randomized, four-arm efficacy trial in which four, distinct exercise prescriptions varying in intensity, frequency, and contraction mode/rate were evaluated: (1) high-resistance concentric-eccentric training (H) 3d/week (HHH); (2) H training 2d/week (HH); (3) 3d/week mixed model consisting of H training 2d/week separated by 1 bout of low-resistance, high-velocity, concentric only (L) training (HLH); and (4) 2d/week mixed model consisting of H training 1d/week and L training 1d/week (HL). Sixty-four randomized subjects (65.5±3.6y) completed the trial. All participants completed the same 4weeks of pre-training consisting of 3d/week followed by 30weeks of randomized RT.

Results: The HLH prescription maximized gains in thigh muscle mass (TMM, primary outcome) and total body lean mass. HLH also showed the greatest gains in knee extension maximum isometric strength, and reduced cardiorespiratory demand during steady-state walking. HHH was the only prescription that led to increased muscle expression of pro-inflammatory cytokine receptors and this was associated with a lesser gain in TMM and total body lean mass compared to HLH. The HL prescription induced minimal muscle regrowth and generally lesser gains in muscle performance vs. the other prescriptions.

Major conclusions: The HLH prescription offers distinct advantages over the other doses, while the HL program is subpar. Although limited by a relatively small sample size, we conclude from this randomized dose-response trial that older adults benefit greatly from 2d/week high-intensity RT, and may further benefit from inserting an additional weekly bout of low-load, explosive RT.

Trial registration: ClinicalTrials.govNCT02442479.

Keywords: Aging; Exercise; Exercise dose; Muscle inflammation; Muscle mass; Muscle strength.

Published by Elsevier Inc.

Figures

Figure 1

Subject recruitment, randomization, and adherence to the four exercise prescriptions.

Figure 2

Effects of the dose-response RT trial on gains in total body lean mass (A), bilateral thigh muscle mass (adjusted to femur length) (B), and bilateral arm muscle mass (C) from wk0 to wk35. *Significant change from pre-training, P

Figure 3

K-means cluster analysis of individual changes in the primary outcome, bilateral thigh muscle mass (TMM) demonstrate a remarkable range of changes in TMM across individuals in each prescription. The center and range of each cluster were as follows: (i) poor responders (n = 25; center = -93 g; range -570 to +187 g), (ii) responders (n = 33; center = +521 g; range +264 to +908 g), and (iii) extreme responders (n = 5; center = +1349 g; range +1015 to +1734 g). While substantial inter-individual heterogeneity was seen, it is noteworthy that all but two of the HLH participants (i.e. 88% of HLH) responded positively (range 280 to 1734 g), including two extreme responders. Such a high responder rate was not the case in any of the other three prescriptions.

Figure 4

Effects of the dose-response RT trial on type I (A) and type II (B) myofiber cross-sectional area. *Significant change from previous time point (main time effect; P

Figure 5

Effects of the dose-response RT trial on myofiber type distribution. *Significant change from previous time point (main time effect; P

Figure 6

Effects of the dose-response RT trial on lower body (A-C) and upper body (D) strength gains. *Significant change from previous time point, P

Figure 7

Effects of the dose-response RT trial on relative mean (A) and peak (B) knee extension power. *Significant change from previous time point, P

Figure 8

Effects of the dose-response RT trial on pro-inflammatory gene expression in the primary muscle group of interest (quadriceps). A) TNF-R gene expression. B) TWEAK-R gene expression. *Significant main time effect from previous time point, P