The molecular underpinnings of muscle plasticity in exercise training

Have you ever wondered what happens to your muscles when you exercise? So do we: our group tries to understand the plasticity of skeletal muscle in exercise training. In our study, we have mapped the epigenetic, transcriptomic and proteomic changes evoked by acute exercise and chronic training.
The molecular underpinnings of muscle plasticity in exercise training
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In our research group, we think that in order to understand pathologies linked to muscle, we have to have a grasp on the physiology, and hence the mechanisms engaged in exercise (reviewed in ref. 1). In our studies, mostly focused on endurance exercise in mice, we obviously want to know whether the interventions worked as intended. Similar to us, mice can react quite differently to training, with high and low responders found in every cohort. Improved endurance can be tested directly, for example by assessing maximal rates of oxygen consumption (VO2max) in treadmill running, or indirectly by quantifying contractile, morphological or metabolic properties such as mitochondrial activity. We however were puzzled by our inability to reliably measure the expression of genes that were proposed as canonical exercise surrogates. In our hands, most of these genes were not reproducible markers and if elevated, only found at very modest levels. Being interested in the mechanistic aspects of muscle plasticity, we therefore decided to embark on a project to comprehensively assess the transcriptome of an exercised muscle at different time points after exhaustion is reached, in our case at 0 hours, 4 hours, 6 hours and 8 hours after the mice stopped to run. Second, even though many studies report results of gene expression analysis in trained muscle, more often than not, these data were obtained shortly after the last bout of exercise was performed, thus consisting of an amalgam of persistent transcriptional adaptations and those acutely elicited by the last exercise bout. We therefore trained mice for 4 weeks, and assessed transcript levels the day after the last exercise bout, thus hopefully “untainted” by acute changes. Finally, we also compared the response of a trained muscle to a bout of exercise with that of an untrained at the same four time points as mentioned above to see whether untrained and trained muscle react the same or differently (ref. 2).

Many of the results of this extensive project were very surprising, at least to us, with the following highlights:

First, we naïvely assumed that the massive morphological, functional and metabolic adaptations that describe a trained muscle have to be maintained by a substantial remodeling of the transcriptome. We, however, only observed roughly 275 genes to be differentially expressed in a trained compared to an untrained muscle in the absence of acute exercise perturbations. Moreover, these genes only poorly correlate with the proteins that exhibit persistent changes in trained muscle.

1.) A trained muscle is only to a relatively small extent defined by transcriptional changes.

Second, the number of genes that are modulated after an endurance exercise bout was much larger, over all four time points about 1’800 genes in the untrained muscle. However, the gene expression that is elicited by an acute bout of exercise in a training-naïve muscle overlaps very little with that found in a trained muscle.

2.) Even though many genes are regulated after an acute bout of exercise in sedentary muscle, the pattern is not predictive of the long-term changes in training.

Third, even more transcripts, approximately 2’470, are altered after an exercise bout in trained animals. Several key differences indicate that the exercise response is markedly affected by the training status: a faster regulation of transcripts that are modulated in both contexts is seen in the trained muscle. Moreover, many genes are exclusively regulated in one or the other muscle, collectively depicting a strong quantitative and qualitative specification of the transcriptomic perturbations by an acute exercise bout with training progression.

3.) A trained muscle responds substantially different to an acute bout of exercise compared to an untrained, with certain gene programs, e.g. those related to inflammation, even reacting in diametrically opposite directions. These networks are predicted to be controlled by selective engagement of transcription factors and coregulators.

Fourth, based on the relatively low number of genes that are persistently modulated in a trained muscle, this training status-dependent transcriptional specification might have additional root causes. By teaming up with Karl Nordström and Jörn Walter of the University of the Saarland, we mapped epigenetic modifications, in this case DNA methylation events. Curiously, many of the genes associated with differentially methylated regions that respond in a training status-specific manner to an acute exercise bout encode transcription factors and coregulators.

4.) A trained muscle might be “primed” by epigenetic modifications to react differently to an exercise bout compared to a training-naïve counterpart.

Finally, we wondered how training adaptations could be brought about mechanistically: our data, and previous results, mainly point to transient engagement of signaling factors and transcriptional regulators in muscle after exercise, while very few candidates with a long-term modulation are known. We therefore repeated the whole experiment of analyzing transcriptome, epigenome and proteome in acute exercise and chronic training in mice with a muscle-specific ablation of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). This co-activator protein is rapidly activated in muscle by exercise, and controls a broad transcriptional network leading to contractile and metabolic changes. We found that in the absence of PGC-1α, not only the acute response to exercise is constricted, but also the long-term training adaptations, even in unperturbed trained muscle in which PGC-1α is not modulated. However, despite massive impairment of transcriptome, epigenome and proteome, muscle-specific PGC-1α knockout mice can improve endurance performance with training, even though at a lower level, and in the absence of classical adaptations such as an elevation of VO2max.

5.) Long-term training adaptations can be brought about by transiently activated factors. However, muscle performance can (submaximally) increase even in unfavorable contexts, potentially attesting to the evolutionary pressure for a robust and redundant system of muscle plasticity in human persistence hunters.

These new insights hopefully help to understand better how muscles react to exercise, and how health benefits associated with training are brought about.

Schematic representation of the molecular exercise response. An acute bout of exercise disrupts the cellular homeostasis of the muscle and initiates a cascade of events including short-term epigenetic and transcriptional changes (change from baseline up = upregulated/hypermethylated; change from baseline down = downregulated/hypomethylated). These alterations promote the restoration of the homeostasis and prepare the muscle for recurrent insults. With repeated exercise bouts over time, a trained muscle is established, hallmarked by morphological and functional adaptations that improve performance. This state is characterized by substantial proteomic remodeling, however in the context of a small number of chronically maintained gene expression modulations. Persistent modification of epigenetic marks prime the response of the trained muscle to recurring acute exercise bouts. Hence, a trained muscle responds more rapidly to an acute maximal exercise bout and shows a prominent repression of genes. Approximately 50% of the upregulated and 85% of the downregulated transcriptome of a trained muscle is specific to this condition and not altered in an untrained muscle post-exercise. Collectively, the molecular response to an acute bout of exercise is training status dependent and substantial qualitative and quantitative changes in gene expression events were observed in trained compared to those that occur in untrained muscle. Figure 7 from ref. 2.

References:

  1. Furrer R, Hawley JA, Handschin C "The molecular athlete: exercise physiology from mechanisms to medals." Physiol Rev. 2023 103(3):1693-1787. doi: 10.1152/physrev.00017.2022.

  2. Furrer R, Heim B, Schmid S, Dilbaz S, Adak V, Nordström KJV, Ritz D, Steurer SA, Walter J, Handschin C "Molecular control of endurance training adaptation in male mouse skeletal muscle." Nat Metab. 2023, manuscript in press. doi: 10.1038/s42255-023-00891-y

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