Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle

Elena Bresciani,Silvia Coco,Vittorio Locatelli,Ramona Meanti,Antonio Torsello,Laura Molteni,Laura Rizzi

doi:10.3390/ijms20184361

Abstract

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia–reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.

Highlights

Calcium (Ca2+) is an intracellular messenger that governs a variety of cellular processes such as gene transcription, cell proliferation, programmed cell death, neurotransmission, and muscle contraction and functioning [1]
Ca2+ pivotal role is the regulation of the excitation–contraction coupling process, but it is involved in protein synthesis and degradation, fiber type shifting, activation of Ca2+-regulated proteases and transcription factors, and mitochondrial adaptation, plasticity, and respiration [1]
This review aims to present the most recent data showing the Growth hormone secretagogues (GHS) involvement in Ca2+ homeostasis, highlighting their therapeutic potential in different conditions characterized by muscle impairment

Summary

Introduction

Calcium (Ca2+) is an intracellular messenger that governs a variety of cellular processes such as gene transcription, cell proliferation, programmed cell death, neurotransmission, and muscle contraction and functioning [1]. The subsequent entry of Ca2+ controls the ryanodine receptors (RyR) in the sarcoplasmic reticulum, allowing a huge release of Ca2+ that favors the cross-bridge between actin and myosin filaments This process is essential for the sarcomere shortening, the contraction of myofibers, and the muscular force generation [1]. A large body of evidence indicates that ghrelin and GHS improve muscle function in several pathological conditions. They show cardioprotective activity both in vitro and in vivo in different experimental models [14,15,16,17,18,19], and humans [20,21]. This review aims to present the most recent data showing the GHS involvement in Ca2+ homeostasis, highlighting their therapeutic potential in different conditions characterized by muscle impairment

GHS Discovery and State of Art

GHS Effects on Muscle

GHS Actions on Cardiac Muscle

GHS Actions on Skeletal Muscle

Conclusions