PI3‐kinase is involved in plasticity of adult myofibers acting as a nodal step that originates divergent pathways for gene expression

Abstract

In skeletal myofibers, transcription of a specific group of genes is regulated by different stimulation frequencies, process known as muscle plasticity. We described IP3‐dependent calcium signals after slow frequency stimulation which were dependent on Cav1.1 and ATP release through pannexin channels. Phosphatidyl inositol 3 kinase (PI3K) is one of the downstream proteins involved in activation of this signaling pathway. Here we present a central role for PI3K in muscle plasticity. We studied expression of sarcomeric (slow and fast troponin I) and metabolic (citrate synthase and enolase) genes, ATP release and IP3 production in adult myofibers from murine FDB muscle. We found a biphasic ATP release and intracellular IP3 increments after 20 Hz stimulation, as well as an increase in TnI‐slow and a decrease in TnI‐fast mRNA levels. In metabolic genes, we observed an increase in citrate synthase and a decrease in enolase mRNA levels. These events were dependent on Cav1.1, pannexin and PI3K. Cav1.1 and Pannexin co‐localize at the T‐tubule membrane. Nevertheless, when fibers were treated with an IP3R blocker (5 μM xestospongin B), we observed an inhibition of TnI gene expression but not of metabolic genes. At 90 Hz, gene expression appears to be independent of IP3‐driven calcium movements. These results show PI3K as a nodal step for plasticity‐related gene expression where signals originated by low frequency stimulation diverge to different routes that control the expression of some sarcomeric genes on one hand and of some metabolic genes on the other.FONDECYT‐1110467/ACT‐1111, AT‐24110054