Monday Article #78: Molecular Adaptations to Exercise

Mind’s racing, heart’s pumping, you’re panting: “Huff, puff, blah, oof, ew”. The breath of exhaustion radiates throughout the surroundings as you come to a stop after a 3-kilometer run. You think to yourself: I’m never going to do this again. The next month, you did it again, but this time, you felt like you could run another lap. What happened?! Did your legs get longer or did you grow another heart? Magic, or is it?

Beyond your visible sweat, and fatiguing exertion, lies a hidden world of cellular transformation, where the microscopic choreography of genes, proteins, and many more molecules synchronize to elicit wonderful adaptations to exercise. Join me, as we unfold the miraculous ballet of molecular adaptations to exercise.

Of course, we won’t have enough space to discuss every single molecule related to adaptations to exercise, so here we discuss the more crucial ones.

The role of protein kinases

By far, one of the most understood molecular mechanisms of adaptation involves adenosine monophosphate kinase (AMPK), which is activated when cellular energy balance is disrupted such as during exercise (Chen et al., 2003). During recovery, our body cells need glucose to rebuild itself and incur molecular adaptations. AMPK seems to play a role in promoting glucose uptake during recovery from exercise by phosphorylating Tbc1d1 protein. This protein acts to delay the glucose transporter GLUT4’s removal from the plasma membrane (Kjøbsted et al., 2019). As a result of higher GLUT4, muscle cells are able to uptake more glucose and produce more energy (Stöckli, Fazakerley and James, 2011). However, some studies using genetic models suggest that in mice that lack AMPK, upregulation of GLUT4 expression still occurs. This, however, was countered by the fact that increasing AMPK levels increased GLUT4 expression in response to chronic exercise (GONG et al., 2011). This could be explained by the fact that, in biology, there are often multiple, complex, and redundant pathways that regulate activity in the body. In mice genetically modified to not have AMPK, exercise activates protein kinase D, which has similar downstream activities of AMPK, but is not activated in wild-type mice (McGee et al., 2014). Hence, overexpression of AMPK could increase adaptations, while underexpression does not affect adaptations due to compensatory mechanisms.

Conversely, AMPK seems to play an indispensable role in mitochondrial biogenesis, evident by AMPK-deficient mice having reduced mitochondrial biogenesis (the process of creating new mitochondria), content, and function (Lantier et al., 2014), as well as less increase in mitochondrial function in response to exercise (Brandauer et al., 2015). AMPK can phosphorylate PGC-1α, leading to mitochondrial biogenesis (Akimoto et al., 2005). Mitophagy (essentially recycling of the mitochondria) is also promoted by AMPK through its activation of the protein kinase Ulk1 (Laker et al., 2017). Together, these mechanisms seem to promote mitochondrial function as well as increase mitochondrial content.

Figure 1: Molecular mechanisms of adaptations involving AMPK. Image taken from AMPK and the Adaptation to Exercise (Spaulding and Yan, 2022).

In a similar fashion, the calcium-calmodulin-dependent protein kinase II (CaMKII) is also activated by elevated cytoplasmic calcium levels, which is present during muscle contractions (Rose and Hargreaves, 2003). CaMKII increases DNA transcription by exporting histone deacetylases (HDAC) out from the nucleus. By removing HDACs, MEF2, a transcriptional activator binds onto the GLUT4 gene, which increases the expression of the GLUT4 gene (Grozinger and Schreiber, 2000). MEF2 also seems to increase PGC-1α expression (Jung and Kim, 2014).

Figure 2: CaMKII-mediated nuclear export of HDACs that allows MEF2 target genes to be transcribed. Image taken from Histone Deacetylase 5 Acquires Calcium/Calmodulin-Dependent Kinase II Responsiveness by Oligomerization with Histone Deacetylase 4 (Backs et al., 2008).

The role of chemokines

Contracting skeletal muscle can release metabolites known as myokines, which have a key role in intermediary metabolism during exercise. For example, the most common exercise-associated molecule is perhaps lactate, which can act as a signaling molecule to activate downstream processes such as hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) (Hunt et al., 2007). HIF-1α has been shown to upregulate the mRNA and protein content of MCT4 (Ullah, Davies and Halestrap, 2006). Higher levels of MCT4 allow fast-twitch muscle cells to export lactate and hydrogen ions (which reduces muscle pH) more effectively, allowing for higher-intensity exercise as the muscle won't get acidic as fast. HIF-1α also increases the expression of glucose transporters, specifically GLUT4 in muscle cells, which facilitates glucose entry into the cell for energy production (Sakagami et al., 2014).

Figure 3: Potential HIF-1 mechanisms. Image taken from Lactate as a Signaling Molecule That Regulates Exercise-Induced Adaptations (