Dr. McCarthy (5) recently produced a review in the Journal dealing with the potential importance that the muscle-specific microRNAs (so-called myomiRs) play during skeletal muscle adaptation. McCarthy put forth the hypothesis that myomiRs play a major role in modulating skeletal muscle phenotype following changes in muscular activity and mainly referred to his own preclinical work to support this hypothesis. For example, to support a role during resistance exercise, McCarthy referred to two short-term muscle overload studies, one being the murine ablation model of functional overload. In each case, he and colleagues found an approximately 40%-50% decrease in miR-1 expression (2,6).
I would like to add to this discussion, as we recently demonstrated that the myomiRs (i.e., miR-1, miR-133a/b, and miR-206) were unaffected by 12 wk of fully supervised resistance exercise training in humans (1). Critically, we also took into account the degree of functional hypertrophy, and still, no relationship was noted. Thus, our data could indicate that the initial myomiR response reviewed by McCarthy subsides when the training period is prolonged.
Beyond this point, it is important to consider what might explain the differences between mouse models and human data. For example, it is accepted that a strong correlation between human and animal experimental data does not always exist and that the value of the compensatory overload synergist ablation model needs some reflection. McCarthy and Esser (6) reported an increase in wet-weight plantaris muscle mass of almost 50% compared with the contralateral muscle after only 7 d of overload. This large and rapid increase in hypertrophic response may not be similar to the physiological conditions in human subjects.
In the human skeletal muscle hypertrophy article published online in 2010 (1), we addressed the novel hypothesis put forward in this review by McCarthy, that is, do robustly expressed miRNAs seem to determine muscle mass gains following resistance training? We demonstrated that successful resistance training-induced muscle hypertrophy (i.e., in "high responders") was associated with selected changes in miRNA abundance, including miR-451. However, the difference in microRNA expression between high responders and low responders to training-induced muscle growth did not include the myomiRs mentioned by McCarthy. This suggests that, although his general thesis that microRNA may be important was valid, our published data provide some relevant details, which would have enhanced his review.
In his review, McCarthy also discussed the impact of endurance exercise training on skeletal muscle myomiR expression. Indeed, we have already provided evidence that myomiR modulation does occur during longer term metabolic adaptation in humans, such as endurance exercise (positive) and insulin resistance (negative) (4,3). More specifically, we demonstrated that two "classical" myomiRs (miR-1 and miR-133a) are significantly downregulated after 6 wk of aerobic exercise training (4) using a combination of gene-chip and real-time quantitative polymerase chain reaction technology. I hope that the results I have shared here can provide more information on this complex topic as we try to sort out the roles of the myomiRs, especially in humans.
James A. Timmons, Ph.D.
The Royal Veterinary College
University of London
London, United Kingdom
1. Davidsen PK, Gallagher IJ, Hartman JW, et al. High responders to resistance exercise training demonstrate differential regulation of skeletal muscle microRNA expression. J. Appl. Physiol.
2. Drummond MJ, McCarthy JJ, Fry CS, Esser KA, Rasmussen BB. Aging differentially affects human skeletal muscle microRNA expression at rest and after an anabolic stimulus of resistance exercise and essential amino acids. Am. J. Physiol. Endocrinol. Metab.
3. Gallagher IJ, Scheele C, Keller P, et al. Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes. Genome Med.
4. Keller P, Vollaard NB, Guttinger S, et al. A transcriptional map of the impact of endurance exercise training on skeletal muscle phenotype. J. Appl. Physiol.
5. McCarthy JJ. The MyomiR network in skeletal muscle plasticity. Exerc. Sport Sci. Rev.
6. McCarthy JJ, Esser KA. MicroRNA-1 and microRNA-133a expression are decreased during skeletal muscle hypertrophy. J. Appl. Physiol.