Difference between revisions of "MetGeneConjugation"

Revision as of 21:01, 3 October 2018

Points of conjugation between metabolic processes associated with aerobic exercise and regulation of gene expression. Ver. 0.5.

Summary remarks

Signal transduction pathways in skeletal muscle

The exercise induced adaptation in skeletal muscle involves a multitude of signalling mechanisms. The process of converting a mechanical signal generated during contraction to a molecular event that promotes adaptation in a muscle cell involves the upregulation of primary and secondary messengers that initiate a cascade of events that result in activation and/or repression of specific signalling pathways regulating exercise-induced gene expression and protein synthesis/degradation. Elucidation of the precise mechanisms that enable skeletal muscle cells to interpret and respond to contraction has proved elusive. Nevertheless, there are numerous putative messengers emerging, including, but not limited to, mechanical stretch, calcium flux, redox state and phosphorylation state, see review (Coffey and Hawley 2007) [1].

Putative Primary Messengers

• Mechanical Stretch
• Calcium
• Redox Potential
• Phosphorylation Potential

Secondary Messengers

• Adenosine Monophosphate Activated Protein Kinase-Mediated Signalling
• Ca2+ Calmodulin-Dependent Kinase/Calcineurin Signalling
• Insulin/Insulin-Like Growth Factor Signalling Pathway
• Cytokine Signalling

At the first stage of modeling, the moderate aerobic exercise model was used, in accordance with our experimental data.

The regulation of gene expression during and after aerobic exercise depends on intencity and volume of exercise. The metabolic adaptations that occur with high-volume training and high-intensity training show considerable overlap, therefore molecular events that signal for these adaptations may be different (Laursen 2010) [2].

The most simplified general view on pathways associated with aerobic exercise is presented on figure:

Fig. 2. (Laursen 2010) [2]. Simplified model of the adenosine monophosphate kinase (AMPK) and calcium–calmodulin kinase (CaMK) signaling pathways, as well as their similar downstream target, the peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a).

For moderate aerobic exercise (70% VO2max, 60 minutes or less) the CAMK pathway is not significant pathway. Therefore, only AMPK signaling pathway was used at the first stage of modeling.

The distinct AMPK signaling pathways may be different for various exercise modes.

Figure 3. (Kjøbsted 2018) [3]. Activation of different AMPK complexes in skeletal muscle is dependent on exercise intensity and duration. In skeletal muscle, LKB1 is the major upstream kinase responsible for the phosphorylation of α2-containing AMPK complexes in response to high/moderate-intensity and short/limited-duration exercise. In contrast, CaMKKβ phosphorylates and activates α1- containing AMPK complexes during long-term exercise at a low intensity. In human vastus lateralis muscle, AMPK activation is restricted to α2β2γ3 heterotrimers during short (up to 20 min) and intense exercise, whereas the α2β2γ1 and α1β2γ1 complexes appear unchanged or even show decreased activation. When exercise is prolonged, α2β2γ1 heterotrimers are activated. During lower-intensity exercise of longer duration, α2β2γ1 and α1β2γ1 complexes are moderately activated. Thus, in skeletal muscle each AMPK heterotrimer combination is regulated in a distinct manner during contraction depending on exercise intensity and duration, which causes a differential functional response.

Therefore, AMPK signaling pathway associated with CaMKKβ was excluded from consideration at the first stage of modeling, in accordance with our experimental data.

References

1. Coffey VG and Hawley JA. The molecular bases of training adaptation. Sports Med. 2007;37(9):737-63. DOI:10.2165/00007256-200737090-00001 | PubMed ID:17722947 | HubMed [1]
2. Laursen PB. Training for intense exercise performance: high-intensity or high-volume training?. Scand J Med Sci Sports. 2010 Oct;20 Suppl 2:1-10. DOI:10.1111/j.1600-0838.2010.01184.x | PubMed ID:20840557 | HubMed [2]
3. Kjøbsted R, Hingst JR, Fentz J, Foretz M, Sanz MN, Pehmøller C, Shum M, Marette A, Mounier R, Treebak JT, Wojtaszewski JFP, Viollet B, and Lantier L. AMPK in skeletal muscle function and metabolism. FASEB J. 2018 Apr;32(4):1741-1777. DOI:10.1096/fj.201700442R | PubMed ID:29242278 | HubMed [3]