"Muscle Memory" Not Mediated By Myonuclear Number?: Secondary Analysis of Human Detraining Data.

In the June 2019 issue of the Journal of Applied Physiology, Psilander and coworkers (12) published a challenging investigation that sought to determine whether “muscle memory” in humans could be explained by the long-term maintenance of myonuclei acquired during hypertrophy. The Gundersen laboratory introduced the concept of myonuclear number conferring muscle memory in 2010 based on work in rodents that underwent synergist ablation overload followed by denervation (1), which has received considerable attention, extending to the lay press (3a). In brief, it is thought that myonuclei acquired from satellite cell fusion during hypertrophic growth remain after detraining when the muscle returns to its pretraining state. If one were to retrain, the need to acquire new myonuclei during hypertrophy would already be met by the previous training stimulus, and growth would proceed more rapidly. The previously acquired myonuclei would serve as a “muscle memory” of prior adaptation. Psilander et al. (12) put forth a tremendous effort to determine whether muscle memory is mediated by myonuclear number, and should be commended for attempting to translate their results from rodent models to humans. Too often, researchers stop short of trying to validate a mechanism in humans, and more work such as this must be undertaken to fully understand skeletal muscle adaptations to exercise. In brief, their study design involved evaluating myonuclear density and muscle size before resistance training, after 10 wk of combined conventional and blood flow-restricted unilateral resistance training that was (according to the authors) specifically designed to elicit myonuclear addition, following 20 wk of detraining, and then again following a short final 5 wk of bilateral training. The contralateral leg served as a control and only underwent the short final training to evaluate the presence of “muscle memory. ” The main take-home messages from their manuscript were 1) the hypothesis could not be tested since myonuclei were not consistently gained across all subjects during the initial training; 2) skeletal muscle can “remember” a degree of strength from an initial 10-wk training period (~60%), even if myonuclear accretion is absent; and 3) there is flexibility within the area that a given myonucleus can govern, or “myonuclear domain,” which is consistent with a large and growing body of literature (6, 7). The authors did well to measure myonuclear accretion using two well-accepted methods (isolated muscle fiber myonuclear counts normalized to sarcomere length and myonuclear density using DAPI and dystrophin immunohistochemistry), which provides confidence in the veracity of their findings. However, in the last decade, a deeper appreciation for heterogeneity in exercise adaptation has emerged (4). Given the reasonably large sample size for a long-term exercise training study employed by Psilander et al. (n 19; 10 female, 9 male), it could be prudent to view their data set through the lens of adaptive heterogeneity. Although myonuclear addition often occurs with resistance training, a secondary analysis is especially salient since it seems that myonuclear accretion may not drive hypertrophy in fully mature muscle (8), and satellite cell fusion could be the result of numerous perturbations, and not hypertrophy per se (3, 6). Fortunately for the field, Psilander and coworkers (12) graciously published their raw data alongside their manuscript (https://doi.org/10.17632/s677jds6t2.1). Given that this study was a significant undertaking, the presentation of raw data gives other researchers the opportunity to interrogate this valuable information and formulate new hypotheses; a practice that is good for science and should be encouraged. When evaluating the single fiber and immunohistochemical myonuclear data, the 19 adult subjects can be clustered into those who presented with myonuclear density values above baseline after training (n 11), and those who did not (n 8). Using single fiber analysis data, significance across three time points was not achieved via one-way repeated measures ANOVA for the 11 subjects that experienced myonuclear accretion (P 0.11), but 7 of 11 subjects experienced a return to baseline myonuclear levels after the detraining period (Fig. 1A, solid lines). Using immunohistochemistry data, statistical significance was achieved for a distinct but overlapping group of 11 subjects (P 0.05), and 9 of 11 subjects experienced an increase followed by a decrease in myonuclear density with training and detraining, respectively (Fig. 1B, solid lines). Seven subjects demonstrated myonuclear accretion according to data from both methods, and six of those showed a reduction in myonuclear number with detraining (P 0.05; Fig. 1, C and D). Furthermore, single muscle fiber volume tracks very closely with single fiber myonuclear counts across time points for those seven subjects, suggesting detrained fibers were not hypernucleated per unit size (Fig. 1E); this is contrary to what Address for reprint requests and other correspondence: K. A. Murach, 900 South Limestone Street, Rm 445, Lexington, KY 40536 (e-mail: kmu236@g. uky.edu). J Appl Physiol 127: 1814–1816, 2019. First published September 12, 2019; doi:10.1152/japplphysiol.00506. 2019.