p300 or CBP is required for insulin-stimulated glucose uptake in skeletal muscle and adipocytes

Abstract

While current thinking posits that insulin signaling to GLUT4 exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle causes a complete loss of insulinstimulated glucose uptake. Similarly, brief (i.e. 1 h) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulates this phenotype in human and rodent myotubes, 3T3-L1 adipocytes, and mouse muscle. Mechanistically, these effects are due to p300/CBP-mediated regulation of GLUT4 exocytic translocation and occurs downstream of Akt signaling. Taken together, we highlight a fundamental role for acetylation and p300/CBP in the direct regulation of insulin-stimulated glucose transport in skeletal muscle and adipocytes.

Insights into post-translational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP

“…Supporting this, recent acetylomics analysis identified two primary categories of acetylated proteins in skeletal muscle cytoplasm: metabolic proteins involved in the generation of ATP and sarcomeric proteins supporting cross-bridge cycling (2). A functional role for p300/CBP in metabolic regulation is supported by our work demonstrating a role for p300/CBP in the regulation of insulin-stimulated glucose uptake (8), whilst a functional role for acetylation in cross-bridge cycling is supported by work in rabbit and drosophila muscle demonstrating modulation of contractile force by acetylation of troponin and actin, respectively (9-11). Considering evidence of a potential non-nuclear role for p300/CBP in the regulation of muscle contractile function, the goal of this work was to evaluate the contribution of mitochondrial function and cross-bridge cycling to the contractile phenotype in i-mPCKO mice, and by extension, to home in on potential mechanisms by which p300/CBP regulate skeletal muscle contractile function.…”

“…The establishment of the i-mPCKO mouse line has been described in detail elsewhere (7, 8). Briefly, i-mPCKO mice were generated through judicious interbreeding of tamoxifen (TMX)-inducible, human α-skeletal actin (HSA)-Cre recombinase mice (12) with Ep300 and Crebbp floxed mice (LoxP sites flanking exon 9 of both genes; (13, 14)).…”

p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson–Gilford progeria syndrome

“…Previously, simultaneous loss of CBP and p300 in skeletal muscle and adipocytes abrogated insulin-stimulated cellular uptake of Glc 33 . However, p300 KO HeLa cells did not exhibit significant differences in Glc uptake levels compared with control cells (Extended Data Fig.…”

The epigenetic regulatory effect of histone acetylation and deacetylation on skeletal muscle metabolism-a review

“…PKB phosphorylates and activates P300/CBP, while P300/CBP acetylates and inactivates PKB. This interaction forms the PKB-P300/CBP axis, influencing insulin signaling, glucose transporter 4 (GLUT4) transport, and metabolism processes ( Martins et al, 2019 ; Martins et al, 2022 ). The mechanism by which P300 mediates skeletal muscle atrophy varies between healthy and diseased individuals.…”