Physical Activity-Dependent Regulation of Parathyroid Hormone and Calcium-Phosphorous Metabolism

Giovanni Lombardi, Ewa Ziemann, Giuseppe Banfi, Sabrina Corbetta, Giovanni Lombardi, Ewa Ziemann, Giuseppe Banfi, Sabrina Corbetta

Abstract

Exercise perturbs homeostasis, alters the levels of circulating mediators and hormones, and increases the demand by skeletal muscles and other vital organs for energy substrates. Exercise also affects bone and mineral metabolism, particularly calcium and phosphate, both of which are essential for muscle contraction, neuromuscular signaling, biosynthesis of adenosine triphosphate (ATP), and other energy substrates. Parathyroid hormone (PTH) is involved in the regulation of calcium and phosphate homeostasis. Understanding the effects of exercise on PTH secretion is fundamental for appreciating how the body adapts to exercise. Altered PTH metabolism underlies hyperparathyroidism and hypoparathyroidism, the complications of which affect the organs involved in calcium and phosphorous metabolism (bone and kidney) and other body systems as well. Exercise affects PTH expression and secretion by altering the circulating levels of calcium and phosphate. In turn, PTH responds directly to exercise and exercise-induced myokines. Here, we review the main concepts of the regulation of PTH expression and secretion under physiological conditions, in acute and chronic exercise, and in relation to PTH-related disorders.

Keywords: PTH; calcium; hyperparathyroidism; hypoparathyroidism; irisin; osteocalcin; phosphate; physical activity; skeletal muscles; vitamin D.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Parathyroid hormone expression and secretion in parathyroid cells. Parathyroid hormone (PTH) is expressed as a prepro-PTH that is then cleaved into mature PTH and stored in granules until secreted. PTH mRNA transcription and PTH secretion are inhibited following the activation of the calcium-sensing receptor (CASR) by extracellular calcium [Ca2+]e, which also stimulates the intracellular inactivation of PTH, into biologically inactive C-terminal fragments, operated throughout the cleavage. Osteocyte-derived fibroblast growth factor (FGF)-23 activates the FGF receptor (FGFR1), heterodimerized with its coreceptor α-Klotho, and inhibits PTH mRNA transcription and PTH protein maturation from prepro-PTH. Finally, 1α,25-dihydroxyvitamin D (1α,25-(OH)2D) binds the intracellular vitamin D receptor (VDR) and inhibits the expression of PTH mRNA. The green arrows indicate PTH expression, the blue arrow indicates a stimulatory pathway, and the red dashed lines indicate inhibitory pathways.
Figure 2
Figure 2
Signaling pathways induced by the activation of the parathyroid hormone receptor. Parathyroid hormone receptor (PTHR)1 is a class II G protein-coupled receptor. Binding of PTH to PTHR1 activates a Gαs protein that activates the adenylate cyclase (AC). AC catalyzes the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). cAMP binds and activates protein kinase A (PKA), which, in turn, phosphorylates the cAMP-responsive element binding protein (CREB) into the nucleus, enabling its binding to the cAMP-responsive element (CRE) on DNA and, thus, activates transcription of specific genes. Through the activation of Gαq, PTHR1 activates membrane-associated phospholipase C (PLC), which cleaves the membrane phospholipid phosphatidylinositol-(4,5)-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol-(1,4,5)-trisphosphate (IP3). IP3 diffuses in the cytoplasm, reaches the endoplasmic reticulum, and induces the release of Ca2+ by activating receptor-gated Ca2+ channels. The Ca2+ released from the endoplasmic reticulum activates Ca2+-dependent responses and, together with the DAG produced by PLC, activates protein kinase C (PKC), which mediates intracellular responses.
Figure 3
Figure 3
Crosstalk between parathyroid glands, bone, and skeletal muscle. The figure schematically summarizes the main interrelationships between PTH, myokines, and osteokines involved in the crosstalk between parathyroid glands bone and skeletal muscle. Parathyroid-released PTH acts on osteoblasts through the PTHR1 receptor; PTH-stimulated RANKL release activated osteoclasts and osteoclasts-mediated bone matrix reabsorption, participating to bone remodeling, while PTH-stimulated osteocalcin release acts on skeletal muscle cells through the GPRC6A receptor. In addition, PTH itself may act on skeletal muscle cells, which express PTHR1. Besides, in response to physical activity muscle cells secreted irisin, which acts on osteoblasts modulating the expression of PTHR1. Lastly, IL-6, which is also released by muscle cells in response to exercise, mediates a modulatory crosstalk between osteoblasts and osteocytes through the receptor gp130. PTH: parathyroid hormone; PTHR1: parathyroid hormone receptor 1; GPRC6A: G protein-coupled receptor 6A; RANK: receptor activator of nuclear factor κ-B; RANKL: ligand of the receptor activator of nuclear factor κ-B; IL-6: interleukin 6; gp130: glycoprotein 130.

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