January 7, 2025
Journal Article

Insights into posttranslational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP

Abstract

Mice with skeletal muscle-specific inducible double knockout of the lysine acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP-response element-binding protein binding protein), referred to as i-mPCKO, demonstrate a dramatic loss of contractile function in skeletal muscle within days of induction, and ultimately mortality. Given that many proteins involved in ATP generation and cross-bridge cycling are acetylated, we investigated whether these processes are dysregulated in skeletal muscle from i-mPCKO mice and thus could underlie the rapid loss of muscle contractile function. Just 4-5 days after inducing knockout of p300 and CBP in skeletal muscle form adult i-mPCKO mice, there was ~90% reduction in ex vivo contractile function in the extensor digitorum longus (EDL) and a ~65% reduction in in vivo ankle dorsiflexion torque, as compared to wildtype (WT; i.e. Cre negative) littermates. Despite the large number of acetylation sites on mitochondrial proteins, there were no significant genotype-driven differences in mitochondrial specific pathway enrichment of the proteome, intermyofibrillar mitochondrial volume or mitochondrial respiratory function. As it relates to cross-bridge cycling, remarkably, the overt loss of contractile function in i-mPCKO muscle was reversed in permeabilized fibers supplied with exogenous Ca2+ and ATP, with active tension being similar between i-mPCKO and WT mice, regardless of Ca2+ concentration. Actin-myosin motility was also similar in skeletal muscle from i-mPCKO and WT mice. In conclusion, neither mitochondrial abundance/function, nor myosin and actin cross-bridge cycling, are the underlying driver of contractile dysfunction in i-mPCKO mice.

Published: January 7, 2025

Citation

Meyer G.A., J. Ferey, J.A. Sanford, L.S. Fitzgerald, A. Greenberg, K. Svensson, and M.J. Greenberg, et al. 2024. Insights into posttranslational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP. Journal of Applied Physiology 136, no. 6:1559 - 1567. PNNL-SA-195576. doi:10.1152/japplphysiol.00156.2024

Research topics