Anabolic and Pro-metabolic Functions of CREB-CRTC in Skeletal Muscle: Advantages and Obstacles for Type 2 Diabetes and Cancer Cachexia.

Rebecca Berdeaux,Chase Hutchins

doi:10.3389/fendo.2019.00535

Abstract

cAMP is one of the earliest described mediators of hormone action in response to physiologic stress that allows acute stress responses and adaptation in every tissue. The classic role of cAMP signaling in metabolic tissues is to regulate nutrient partitioning. In response to acute stress, such as epinephrine released during strenuous exercise or fasting, intramuscular cAMP liberates glucose from glycogen and fatty acids from triglycerides. In the long-term, activation of Gs-coupled GPCRs stimulates muscle growth (hypertrophy) and metabolic adaptation through multiple pathways that culminate in a net increase of protein synthesis, mitochondrial biogenesis, and improved metabolic efficiency. This review focuses on regulation, function, and transcriptional targets of CREB (cAMP response element binding protein) and CRTCs (CREB regulated transcriptional coactivators) in skeletal muscle and the potential for targeting this pathway to sustain muscle mass and metabolic function in type 2 diabetes and cancer. Although the muscle-autonomous roles of these proteins might render them excellent targets for both conditions, pharmacologic targeting must be approached with caution. Gain of CREB-CRTC function is associated with excess liver glucose output in type 2 diabetes, and growing evidence implicates CREB-CRTC activation in proliferation and invasion of different types of cancer cells. We conclude that deeper investigation to identify skeletal muscle specific regulatory mechanisms that govern CREB-CRTC transcriptional activity is needed to safely take advantage of their potent effects to invigorate skeletal muscle to potentially improve health in people with type 2 diabetes and cancer.

Highlights

Many chronic human diseases are either caused or accompanied by skeletal muscle dysfunction and loss of muscle mass [1]
We focused discussion on articles with mechanistic findings related to skeletal muscle autonomous and non-autonomous functions of cAMP response element binding protein (CREB)-CREB regulated transcriptional coactivator (CRTC), their target genes and upstream activating Gscoupled G Protein-coupled receptor (GPCR) in skeletal muscle hypertrophy, metabolism, and cancer
Long known for its role as a second messenger coordinating skeletal muscle nutrient utilization with functional demands, cyclic adenosine monophosphate (cAMP) has been appreciated for its ability to stimulate hypertrophic growth and long-term metabolic adaptation

Summary

INTRODUCTION

Many chronic human diseases are either caused or accompanied by skeletal muscle dysfunction and loss of muscle mass [1]. CAMP signaling simultaneously activates CRTCs (CREB regulated transcriptional coactivators), which interact with CREB to drive transcription of cAMP-regulated genes [17] Because of their implicated functions in muscle hypertrophy and metabolic adaptions to exercise, CREB, CRTCs, and their target genes represent potential therapeutic targets to sustain skeletal muscle mass and function in diabetes and cancer. This mini-review focuses on the known roles and transcriptional targets of CREB and CRTCs in regulation of skeletal muscle function and adaptation. We highlight how the transcriptional activity of CREB-CRTC regulates muscle function and explore dysregulation of the cAMP-CREB-CRTC pathway in skeletal muscles in the context of type 2 diabetes and cancer cachexia. Pathway to improve muscle health and avoid off-target effects in individuals with metabolic disease or cancer

Literature Search Strategy

CONCLUDING REMARKS