Muscle signaling in LRT. A proposed sequence of signaling and transcriptional regulatory events that occurred in LRT was generated
based on bioinformatic analysis of exercise-stimulated transcription and Western blotting analysis of skeletal muscle samples.
In response to acute exercise, LRT have hyperactivation of JNK and P38 MAPK, leading to elevated phosphorylation of SMAD2
in its linker region at Ser245/250/255. Increased exercise-induced SMAD2 linker region phosphorylation results in altered
gene expression by its binding partners SMAD3 and CREB1. Constitutive activation of CaMKII by phosphorylation of its autoregulatory
site Thr286 also may contribute to altered transcription in LRT via its regulatory effects on HDAC and CREB1. Altered signal
transduction and gene transcription likely lead to impaired remodeling of skeletal muscle in LRT, which, in turn, may contribute
to decreased exercise capacity and whole-body metabolic dysfunction. ERK, extracellular signal–regulated kinase; P38, p38
mitogen-activated protein kinase; PM, plasma membrane; SMAD, mothers against decapentaplegic homolog.