Chapter Four - Myokines: The endocrine coupling of skeletal muscle and bone
Introduction
According to the classical view, the bone tissue solves three main functions: structural (e.g., sustainment of the body, protection of visceral organs, and reciprocal movements of bony segments), dynamic storage of calcium and phosphate, and hematopoiesis. These functions rely on the ability of the bone to integrate the information brought by endogenous (mainly hormonal and inflammatory) and exogenous (biomechanical load, diet, vitamin D) stimuli and, consequently, to adapt its composition, shape, and strength. Adaptation results from the shift of the equilibrium between bone resorption and formation. The former consists in the removal of old, damaged, or functionally obsolete tissue, and is mediated by monocyte-derived multinucleated osteoclasts, whereas the latter consists in the deposition of new functional extracellular matrix (ECM), mediated by mesenchymal-derived osteoblasts. These two processes, although opposite, are strikingly co-regulated causing a continuous turnover that makes the bone a very dynamic tissue. Under opportune stimulation, bone remodeling starts with osteoclasts resorbing ECM from the surface to the deep regions toward a resorbing cone, while activated osteoblasts secrete new ECM along the same direction. Osteoblasts buried in their own ECM further differentiate into osteocytes, the main bone cell population which is involved in the biomechanical sensing of load and the regulation of turnover [1]. Mechanical load plays a pivotal role in bone metabolism and biomechanical sensing has important systemic impacts [2]. When mechanically loaded, bone signals a need of energy to sustain bone formation; the apposition of new bone matrix allow the optimization of tissue architecture based on the new environment (i.e., the external load) [3]. When unloaded, instead, bone signals low energy need that promotes resorption (or, reduced bone turnover) and this allows the preservation of energy for other essential activities [4]. As a confirmation of this role in the systemic regulation of the energy usage, bone has been recently recognized to be, other than an endocrine target, an endocrine organ itself that triggers specific responses in other tissues. Indeed, several molecules, previously described as markers of bone turnover, are now recognized as hormones [5].
Physical activity (PA) is the main physiological stimulus for bone anabolism (and/or catabolism) and, besides the direct effect of loading, a key effector of this action is the skeletal muscle (SKM). SKM, indeed, applies the force onto the bone segments (lever arms) allowing their reciprocal movements around the joint (i.e., the fulcrum). Thus, the muscle directly exercises a force (traction) on the bone segment on which it is inserted [6]. However, the direct mechanical interaction is not the only way by which SKM affects bone metabolism: as for the bone, also for the muscle an important endocrine function has been recognized. The daily activity results in a continuous modulation of the SKM cells metabolic activity and, hence, on their endocrine function affecting, in turn, the homeostatic response of all body organs, including bone. On the other hand, the daily loading cycles directly affect bone metabolism and its endocrine function with impact on whole-body homeostasis, including SKM. Hence, as a vicious cycle, bone is, at the same time, a target and an effector of the PA-dependent metabolic activation [4].
In this review article, we illustrate the exercise-induced modulation of hormones and cytokines, namely myokines, that mediate the cross-talk between SKM and bone, as well as other tissues, such as AT, to stimulate the homeostatic adaptation. Moreover, we describe the role of these endocrine axes in counterbalancing the systemic chronic low-grade metabolic inflammation, in aging and disease, a condition further aggravated by physical inactivity.
Section snippets
The bone-muscle unit
Bone and muscle are integrated organs sharing several functions (e.g., in locomotion and growth) and they both carry out endocrine functions [5], [7]. It is thus not surprising that, from development to maintenance, these two organs work in concert, regulate each other, and are co-regulated by several factors [8]. This co-regulation acts on three different but strikingly interrelated levels: mechanical, ontogenetic and endocrine [9]. The multiple evidences about this multilevel relationship
The bone-muscle unit and physical activity
In order to better address the reader, here is a brief introduction to some concepts of exercise physiology.
Two major types of muscle actions can be distinguished depending on the final work output. The isometric (static) action happens when the muscle generates a force without changing its length as in the case of the application of an external force (weight) exceeding the force generated by the muscle; in this case, despite the energetic cost of this action, since no movement results, no work
Myokines and bone
The SKM tissue is composed of multinucleated cells (myofibers) that generate forces, through the contraction of the sarcomere protein complex. Muscle cells are responsible for body posture, locomotion and, as in the case of the smooth muscle, for the movement of internal organs. SKMs comprise approximately 40% of the total body weight [73]. During the past 30 years, the role of exercise in modulating the immune system functions has been widely demonstrated. The first observations highlighted an
Chronic low-grade inflammation, aging and obesity
Physical inactivity is a global health issue and represents the fourth cause of death worldwide, according to World Health Organization (WHO). The WHO recommended a minimum of 150 min/week of moderate to vigorous aerobic PA and individuals who do not comply with this recommendation are considered physical inactive [243]. Regular PA is considered an effective non-pharmacological treatment option for a number of metabolic diseases and has been associated with reduced risk of type 2 diabetes
Conclusion and future research directions
Skeletal muscle is an endocrine organ that directly release myokines to regulate the function and the fate of virtually all cell types, among them bone tissue cells, including osteoblasts, osteoclasts, osteocytes and BMSCs. Indeed, besides mediating cross-talk between SKM and bone, muscle-released myokines affect the function of other organs and tissues, including liver, intestine and AT, that in turn release cytokines and hormones (i.e., adipokines or hepatokines) responsible for the
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