MetGeneConjugation

Points of conjugation between metabolic processes associated with aerobic exercise and regulation of gene expression. Ver. 1.0.

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. Concomitant with the vastly different functional outcomes induced by diverse exercise modes, the genetic and molecular mechanisms of adaptation are distinct. 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

It is unlikely that these primary signalling messengers act in isolation, and probably results in an intricate multifaceted signal with redundancy and cross-talk. Following initiation of the primary signal, additional kinases/phosphatases are activated to mediate the exercise-induced signal. Numerous signalling cascades exist in mammalian cells and these pathways are highly regulated at multiple levels, with substantial cross-talk between pathways producing a highly sensitive, complex transduction network. In modeling context the next pathways in skeletal muscle are taken to consideration: the AMPK, calmodulin/calcineurin, IGF and NFkB-Tumour necrosis factor-а (TNFa) signalling pathways. 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 and high intencity 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-γ coactivator-1α (PGC-1α).

The AMPK directly phosphorylate the PGC-1α (Jäger 2007) [3]), a transcriptional coactivator that has been described by some as the ‘‘master switch’’ for mitochondrial biogenesis (Adhihetty et al., 2003) [4].

In skeletal muscle adapted to aerobic training, intensity-dependent activation of mitochondrial biogenesis after acute exercise is associated primarily with the AMP-activated protein kinase/PGC-1α pathway, expression of PGC-1α-regulated genes, and expression of PPARGC1A from the alternative (distal) inducible promoter regulated by the cAMP response element-binding protein 1-related transcription factors and their coactivators exercise (Popov ‎2018) [5].

For moderate and high intencity interval aerobic exercise (50-100% of anaerobic threshold, 60 minutes) 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) [6]. 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.

The extended data for AMPK, LKB1 and CaMKKβ in modeling context are present at next Wiki pages: AMPK, LKB1, CaMKKβ

The review of the skeletal muscle metabolism models is present at next Wiki page: Muscle_models

Phenotype-Signaling Feedback

The chronic contractile activity, in the form of repeated bouts of endurance exercise, results in the altered expression of a wide variety of gene products, leading to an altered muscle phenotype with improved fatigue resistance. This improved endurance is highly correlated with the increase in muscle mitochondrial density and enzyme activity, referred to as ‘mitochondrial biogenesis’ (Adhihetty et al., 2003) [4].

The improved endurance, the increase in muscle mitochondrial density and the changes in abundance of variety signal proteins, results in the altered signaling pathways activity. For example, contraction-induced AMPKα phosphorylation was blunted in mouse skeletal muscle, in which the oxidative capacity had been enhanced (Ljubicic 2009) [7], inverse relationships were observed between mitochondrial volume and some kinase proteins content and their basal levels of phosphorylation. Thus, mitochondrial content and oxidative capacity are determinants of the activation of signaling proteins important to muscle plasticity. The attenuation of kinase phosphorylation in muscle with high mitochondrial content suggests that these proteins may require a greater stimulus input for activation to propagate these cues downstream to evoke phenotypic adaptations.

In human long term training can lead to blunted signaling response also (Yu 2003). The AMPKa2 phosphorylation and activity and p38 MAPK phosphorylation in response to cycling exercise undertaken at the same relative intensity was greater in the untrained control subjects than in welltrained individuals, even though the less-trained subjects completed 50 % of the exercise protocol performed by the athletes.

The Phenotype-Signaling Feedback is intriguing feature for modeling of the long-term adaptation.

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 |
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 |
3. Jäger S, Handschin C, St-Pierre J, and Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12017-22. DOI:10.1073/pnas.0705070104 |
4. Adhihetty PJ, Irrcher I, Joseph AM, Ljubicic V, and Hood DA. Plasticity of skeletal muscle mitochondria in response to contractile activity. Exp Physiol. 2003 Jan;88(1):99-107. DOI:10.1113/eph8802505 |
5. Popov DV. Adaptation of Skeletal Muscles to Contractile Activity of Varying Duration and Intensity: The Role of PGC-1α. Biochemistry (Mosc). 2018 Jun;83(6):613-628. DOI:10.1134/S0006297918060019 |
6. 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 |
7. Ljubicic V and Hood DA. Specific attenuation of protein kinase phosphorylation in muscle with a high mitochondrial content. Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E749-58. DOI:10.1152/ajpendo.00130.2009 |
8. Yu M, Stepto NK, Chibalin AV, Fryer LG, Carling D, Krook A, Hawley JA, and Zierath JR. Metabolic and mitogenic signal transduction in human skeletal muscle after intense cycling exercise. J Physiol. 2003 Jan 15;546(Pt 2):327-35. DOI:10.1113/jphysiol.2002.034223 |