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How does gene expression affect skeletal muscle adaptations to exercise and training?

This is an excerpt from Biochemistry Primer for Exercise Science-5th Edition by A. Russell Tupling,Peter M. Tiidus & Michael E. Houston.

Regulation of Gene Expression in Exercise and Training
The control of gene expression in skeletal muscle has been an area of active research for many years, helping us understand how muscles adapt to improve their performance with exercise training. Exercise and training are generally grouped into aerobic or endurance and power or strength activities or are viewed along a continuum based on the load of contraction or intensity (low→high) and the duration (long→short) of exercise. Endurance exercise lies at one end of the continuum, being performed at a relatively low load or intensity over a long duration, and strength or resistance exercise lies at the opposite end of the continuum, being performed at a relatively high load or intensity for a short duration. In contrast to endurance exercise, which is typically performed continuously as one relatively long bout, interval exercise involves repeated bouts of relatively intense activity interspersed with short periods of recovery. Two common interval training methods are high-intensity interval training (HIIT) and sprint interval training (SIT). HIIT is defined as near-maximal efforts (e.g., 80%-95% of maximal heart rate), and SIT is defined as all-out or supramaximal efforts (e.g., intensities equal to or greater than the power output that would elicit V̇O₂max). We have long known that endurance training induces metabolic adaptations in skeletal muscle and, importantly, increases the content of mitochondrial proteins involved in oxidative phosphorylation, without any significant changes in contractile proteins or muscle hypertrophy. Recently, many studies have shown that HIIT and SIT also both increase skeletal muscle mitochondrial content to the same degree or more compared to classical endurance training (reviewed in MacInnis and Gibala 2017). On the other hand, high-intensity resistance training increases the mean cross-sectional area of muscle fibers and induces muscle hypertrophy by increasing the content of contractile proteins but without a notable effect on mitochondrial proteins. This tells us that the stimulus induced by the specific exercise activity must selectively modulate the transcription of some muscle genes, leading to increased levels of mRNA and thus proteins. Muscle hypertrophy and mitochondrial adaptations are the result of cumulative effects of repeated acute bouts of high-intensity resistance exercise and endurance or interval exercise, respectively. The primary question is how the training stress is linked to the activation of key genes. Kristian Gundersen (2011) suggests that an “excitation-transcription coupling” must exist in skeletal muscle, whereby primary signals generated by muscle contractions are deciphered by intracellular molecules that act as sensors and are transmitted via signaling pathways that ultimately regulate transcription factors, coactivators, and corepressors of specific genes (i.e., contractile protein and mitochondrial protein genes). A simplistic flow chart for how muscle contraction signals could be processed by the muscle fiber to alter gene transcription is given in figure 3.26. The key premise is that acute exercise causes disruptions in systemic and cellular homeostasis generating signals that are sensed and transmitted within the muscle to activate proteins that regulate gene expression, resulting in cellular and molecular adaptations that attenuate perturbations in homeostasis with successive exercise bouts.

Mitochondrial Adaptations to Endurance Training, HIIT, and SIT
Many muscle contraction signals associated with different types of exercise may serve as primary signals in excitation-transcription coupling, resulting in the adaptations to training noted previously. However, it is becoming increasingly apparent that oscillations in cytoplasmic [Ca²⁺], [AMP]/[ATP], and reactive oxygen species (ROS) are key signals that correlate with the frequency, duration, and intensity of contractions and are the primary signals that activate signaling pathways in skeletal muscle that control the expression of several transcription factors and mitochondrial proteins with endurance training, HIIT, and SIT. See chapters 4 and 5 for more information on the importance of AMP/ATP, ROS, and calcium changes in muscle during exercise, as well as their regulation.

In skeletal muscle, two primary Ca²⁺-dependent transcriptional pathways that are activated with endurance exercise, HIIT, and SIT are the Ca²⁺-calmodulin-dependent serine/threonine protein phosphatase, calcineurin (CaN), and the Ca²⁺-calmodulin-dependent kinase II and IV (CaMKII and CaMKIV) pathways (Chin 2010). One of the substrates for CaN is a transcription factor known as NFAT (nuclear factor of activated T cells). When activated by Ca²⁺-calmodulin, it is possible for CaN to dephosphorylate NFAT, allowing it to enter the nucleus and bind to its response element in the control region of a number of its target genes in skeletal muscle. One of the substrates for CaMK is a class of HDAC enzymes that, when dephosphorylated, interact with and inhibit a transcription factor called myocyte-enhancer factor 2 (MEF2). CaMK induces nuclear export of these HDACs through phosphorylation, which increases MEF2-dependent transcription.

HDACs can also be phosphorylated by AMPK (McGee and Hargreaves 2011). As described in the Next Stage section in chapter 2, AMPK is activated during metabolic stress by increased [AMP]/[ATP]. Several studies have shown that AMPK is activated in skeletal muscle in response to endurance exercise, HIIT, and SIT. Therefore, AMPK signaling also contributes to MEF2-dependent transcription and altered gene expression with endurance training, HIIT, and SIT. Moreover, AMPK signaling promotes mitochondrial biogenesis in skeletal muscle through its effects on PGC-1α expression and activity. As the PGC-1α gene is regulated by MEF2, which is activated by both AMPK and Ca²⁺ signaling pathways, its expression is increased with exercise in an intensity-dependent manner, which likely enhances the adaptive response to subsequent exercise bouts. As mentioned previously, PGC-1α is a transcriptional coactivator that is considered to be a major regulator of mitochondrial biogenesis (reviewed in Uguccioni, D’Souza, and Hood 2010). PGC-1α interacts with several transcription factors, such as nuclear respiratory factors (NRF)-1 and -2, the estrogen-related receptor ERRα, and PPARs, that induce the expression of mitochondrial genes. PGC-1α interaction with NRF1 also promotes the expression of mitochondrial transcription factor A (Tfam), which in turn mediates mtDNA transcription, thereby connecting the expression of the mitochondrial and nuclear genomes. When it is bound to a transcription factor, PGC-1α binds several HAT enzymes that, as discussed previously, remodel histones on chromatin, thereby allowing greater access of the transcriptional machinery to DNA for initiation of transcription.

Another important signaling pathway involved in the adaptive response of skeletal muscle to endurance exercise, HIIT, and SIT is the mitogen-activated protein kinase (MAP kinase, or MAPK) pathway. The word mitogen refers to something that stimulates cell proliferation (mitosis), but only some of the actions of the MAP kinases ultimately lead to the formation of new cells. Activation of the p38γ MAPK in skeletal muscle phosphorylates and activates PGC-1α but also activates other transcription factors, namely MEF2 and activating transcriptional factor 2 (ATF2), that increase transcription of the PGC-1α gene. Increased ROS production and CaMK activity appear to be important for activating p38γ MAPK during exercise. The major signaling pathways underlying endurance exercise–, HIIT-, or SIT-induced adaptation in skeletal muscle (see figure 3.27) have been the subject of several reviews (McGee and Hargreaves 2011; Perry and Hawley 2017; MacInnis and Gibala 2017).

Booth and Neufer (2005) summarized studies that all monitored gene expression in subjects over the course of a short-term one-legged endurance training program. They described the response of genes in terms of how rapidly they responded, the duration of the response, and the peak of the response based on mRNA transcript levels. Genes that were turned on very quickly but transiently were described as “stress response genes.” These coded for proteins, such as transcription factors, whose content was rapidly elevated in a number of models under high-stress conditions. A second category of genes, the “metabolic priority genes,” demonstrated peak expression several hours after the exercise-training bout. Genes in this latter category coded for enzymes that played regulatory roles in carbohydrate metabolism. The third gene category, “metabolic/mitochondrial enzymes,” was slower to respond and had a lower peak response, but the response persisted over a longer period of time. These genes coded for mitochondrial proteins involved in oxidative phosphorylation. Studies such as those summarized by Booth and Neufer (2005) remind us that there are priorities in the transcription of genes, the ultimate effect of which is to enhance the ability to respond to further training stimuli.

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