Excitation‐transcription coupling in skeletal muscle: the molecular pathways of exercise

Abstract

Muscle fibres have different properties with respect to force, contraction speed, endurance, oxidative/glycolytic capacity etc. Although adult muscle fibres are normally post-mitotic with little turnover of cells, the physiological properties of the pre-existing fibres can be changed in the adult animal upon changes in usage such as after exercise. The signal to change is mainly conveyed by alterations in the patterns of nerve-evoked electrical activity, and is to a large extent due to switches in the expression of genes. Thus, an excitation-transcription coupling must exist. It is suggested that changes in nerve-evoked muscle activity lead to a variety of activity correlates such as increases in free intracellular Ca2+ levels caused by influx across the cell membrane and/or release from the sarcoplasmatic reticulum, concentrations of metabolites such as lipids and ADP, hypoxia and mechanical stress. Such correlates are detected by sensors such as protein kinase C (PKC), calmodulin, AMP-activated kinase (AMPK), peroxisome proliferator-activated receptor δ (PPARδ), and oxygen dependent prolyl hydroxylases that trigger intracellular signaling cascades. These complex cascades involve several transcription factors such as nuclear factor of activated T-cells (NFAT), myocyte enhancer factor 2 (MEF2), myogenic differentiation factor (myoD), myogenin, PPARδ, and sine oculis homeobox 1/eyes absent 1 (Six1/Eya1). These factors might act indirectly by inducing gene products that act back on the cascade, or as ultimate transcription factors binding to and transactivating/repressing genes for the fast and slow isoforms of various contractile proteins and of metabolic enzymes. The determination of size and force is even more complex as this involves not only intracellular signaling within the muscle fibres, but also muscle stem cells called satellite cells. Intercellular signaling substances such as myostatin and insulin-like growth factor 1 (IGF-1) seem to act in a paracrine fashion. Induction of hypertrophy is accompanied by the satellite cells fusing to myofibres and thereby increasing the capacity for protein synthesis. These extra nuclei seem to remain part of the fibre even during subsequent atrophy as a form of muscle memory facilitating retraining. In addition to changes in myonuclear number during hypertrophy, changes in muscle fibre size seem to be caused by alterations in transcription, translation (per nucleus) and protein degradation.

Irisin and FNDC5: effects of 12-week strength training, and relations to muscle phenotype and body mass composition in untrained women

“…This may be linked to the fact that low-intensity every-day activities such as walking, which preferentially activate type 1 fibers, may lead to increased nuclear translocation of PGC1α, in turn leading to the observed fiber-specific FNDC5 expression. Indeed, slow-fibre patterned electrical activity has been shown to be capable of resulting in increased PGC1α protein abundance in both rodents and humans (Irrcher et al 2003;Gundersen 2011;Adams et al 2011). Alternatively, it may point to a housekeeping-resembling manner of regulation of irisin biology, wherein FNDC5 expression and irisin secretion is a passive consequence of muscle fiber composition.…”

Are cultured human myotubes far from home?

“…The experimental model of chronic low-frequency stimulation (CLF) in animals has shown such transitions in rabbits and rats (for review see (Pette and Vrbova, 1999)). The plasticity of skeletal muscle in general has been thoroughly reviewed by others (Fluck and Hoppeler, 2003, Gundersen, 2010, Schiaffino and Reggiani, 2011.…”

Excitation-Contraction Coupling and Excitation-Transcription Coupling in Skeletal Muscle

“…The molecular signals coupling excitation and contraction also regulate the transcriptional activity of the cell over a much longer time scale by a process known as excitation-transcription (E-T) coupling [4]. In skeletal muscle E-T coupling, Ca 2+ released from internal stores during E-C coupling triggers communication to the nucleus to regulate gene expression and thereby shape the transcriptome [4,5].…”

“…In skeletal muscle E-T coupling, Ca 2+ released from internal stores during E-C coupling triggers communication to the nucleus to regulate gene expression and thereby shape the transcriptome [4,5]. In response to external cues, such as electrical activity at the neuromuscular junction, skeletal muscle exhibits plastic changes, reprogramming gene expression to sustain a specific muscle performance by activating signaling pathways according to excitation pattern [6][7][8][9].…”

“…The two most well characterized Ca 2+ -regulated transcription pathways in skeletal muscle are mediated by the phosphatase calcineurin (CaN) and the kinase, CaMKII, both dependent on Ca 2+ -calmodulin (CaM) [4,5,11,13]. The CaM-CaN pathway activates the transcription factors nuclear factor of activated T-cells and myocyte enhancer factor 2 (MEF2) to control slow-type muscle fiber gene expression [9,14,15].…”