Chapter Four - Myokines: The endocrine coupling of skeletal muscle and bone

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Abstract

Bone and skeletal muscle are integrated organs and their coupling has been considered mainly a mechanical one in which bone serves as attachment site to muscle while muscle applies load to bone and regulates bone metabolism. However, skeletal muscle can affect bone homeostasis also in a non-mechanical fashion, i.e., through its endocrine activity. Being recognized as an endocrine organ itself, skeletal muscle secretes a panel of cytokines and proteins named myokines, synthesized and secreted by myocytes in response to muscle contraction. Myokines exert an autocrine function in regulating muscle metabolism as well as a paracrine/endocrine regulatory function on distant organs and tissues, such as bone, adipose tissue, brain and liver.

Physical activity is the primary physiological stimulus for bone anabolism (and/or catabolism) through the production and secretion of myokines, such as IL-6, irisin, IGF-1, FGF2, beside the direct effect of loading. Importantly, exercise-induced myokine can exert an anti-inflammatory action that is able to counteract not only acute inflammation due to an infection, but also a condition of chronic low-grade inflammation raised as consequence of physical inactivity, aging or metabolic disorders (i.e., obesity, type 2 diabetes mellitus).

In this review article, we will discuss the effects that some of the most studied exercise-induced myokines exert on bone formation and bone resorption, as well as a brief overview of the anti-inflammatory effects of myokines during the onset pathological conditions characterized by the development a systemic low-grade inflammation, such as sarcopenia, obesity and aging.

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

References (303)

  • M.L. Bareither et al.

    Bone mineral density of the proximal femur is not related to dynamic joint loading during locomotion in young women

    Bone

    (2006)
  • J.N. Dowthwaite et al.

    Mechanical loading during growth is associated with plane-specific differences in vertebral geometry: a cross-sectional analysis comparing artistic gymnasts vs. non-gymnasts

    Bone

    (2011)
  • R.S. Rector et al.

    Participation in road cycling vs running is associated with lower bone mineral density in men

    Metabolism

    (2008)
  • A. Heinonen et al.

    Bone mineral density of female athletes in different sports

    Bone Miner.

    (1993)
  • V. Veverka et al.

    Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation

    J. Biol. Chem.

    (2009)
  • W. Qin et al.

    The central nervous system (CNS)-independent anti-bone-resorptive activity of muscle contraction and the underlying molecular and cellular signatures

    J. Biol. Chem.

    (2013)
  • E. Kellum et al.

    Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5 expression, and callus bone volume

    Bone

    (2009)
  • H. Amthor et al.

    Follistatin complexes myostatin and antagonises myostatin-mediated inhibition of myogenesis

    Dev. Biol.

    (2004)
  • Z. Huang et al.

    Myostatin: a novel insight into its role in metabolism, signal pathways, and expression regulation

    Cell. Signal.

    (2011)
  • M.W. Hamrick et al.

    Loss of myostatin (GDF8) function increases osteogenic differentiation of bone marrow-derived mesenchymal stem cells but the osteogenic effect is ablated with unloading

    Bone

    (2007)
  • Y. Qin et al.

    Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: a novel mechanism in muscle-bone communication

    J. Biol. Chem.

    (2017)
  • V. Camozzi et al.

    Role of biochemical markers of bone remodeling in clinical practice

    J. Endocrinol. Invest.

    (2007)
  • J. Xu et al.

    Effects of exercise on bone status in female subjects, from young girls to postmenopausal women: an overview of systematic reviews and meta-analyses

    Sports Med.

    (2016)
  • V. Sansoni et al.

    Bone turnover response is linked to both acute and established metabolic changes in ultra-marathon runners

    Endocrine

    (2017)
  • G. Lombardi et al.

    Implications of exercise-induced adipo-myokines in bone metabolism

    Endocrine

    (2016)
  • G. Karsenty et al.

    The contribution of bone to whole-organism physiology

    Nature

    (2012)
  • N. Felsenthal et al.

    Mechanical regulation of musculoskeletal system development

    Development

    (2017)
  • B.K. Pedersen et al.

    Muscles, exercise and obesity: skeletal muscle as a secretory organ

    Nat. Rev. Endocrinol.

    (2012)
  • I. Zofkova

    Hormonal aspects of the muscle-bone unit

    Physiol. Res.

    (2008)
  • L.H. Bogl et al.

    An investigation into the relationship between soft tissue body composition and bone mineral density in a young adult twin sample

    J. Bone Miner. Res.

    (2011)
  • S.A. Jackowski et al.

    Does lean tissue mass accrual during adolescence influence bone structural strength at the proximal femur in young adulthood?

    Osteoporos. Int.

    (2014)
  • H.M. Frost

    Bone's mechanostat: a 2003 update

    Anat. Rec. A Discov. Mol. Cell Evol. Biol.

    (2003)
  • C.T. Rubin

    Skeletal strain and the functional significance of bone architecture

    Calcif. Tissue Int.

    (1984)
  • J.S. Price et al.

    Role of endocrine and paracrine factors in the adaptation of bone to mechanical loading

    Curr. Osteoporos. Rep.

    (2011)
  • G. Lombardi et al.

    Physical activity and bone health: what is the role of immune system? A narrative review of the third way

    Front. Endocrinol.

    (2019)
  • B.K. Hall et al.

    Paralysis and growth of the musculoskeletal system in the embryonic chick

    J. Morphol.

    (1990)
  • A. Hosseini et al.

    The effects of paralysis on skeletal development in the chick embryo. I. General effects

    J. Anat.

    (1991)
  • J.I. Rodriguez et al.

    Morphological changes in long bone development in fetal akinesia deformation sequence: an experimental study in curarized rat fetuses

    Teratology

    (1992)
  • J.A. Germiller et al.

    Structure and function of embryonic growth plate in the absence of functioning skeletal muscle

    J. Orthop. Res.

    (1997)
  • I. Rot-Nikcevic et al.

    Myf5-/- :MyoD-/- amyogenic fetuses reveal the importance of early contraction and static loading by striated muscle in mouse skeletogenesis

    Dev. Genes Evol.

    (2006)
  • C. Gomez et al.

    Absence of mechanical loading in utero influences bone mass and architecture but not innervation in Myod-Myf5-deficient mice

    J. Anat.

    (2007)
  • N.C. Nowlan et al.

    Mechanobiology of embryonic skeletal development: insights from animal models

    Birth Defects Res. C Embryo Today

    (2010)
  • K.A. Roddy et al.

    Mechanical influences on morphogenesis of the knee joint revealed through morphological, molecular and computational analysis of immobilised embryos

    PLoS One

    (2011)
  • A. Sharir et al.

    Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis

    Development

    (2011)
  • S.E. Utvag et al.

    Influence of extensive muscle injury on fracture healing in rat tibia

    J. Orthop. Trauma

    (2003)
  • H. Kaufman et al.

    The biological basis of the bone-muscle inter-relationship in the algorithm of fracture healing

    Orthopedics

    (2008)
  • P. Krustrup et al.

    Long-term musculoskeletal and cardiac health effects of recreational football and running for premenopausal women

    Scand. J. Med. Sci. Sports

    (2010)
  • H. Kaji

    Linkage between muscle and bone: common catabolic signals resulting in osteoporosis and sarcopenia

    Curr. Opin. Clin. Nutr. Metab. Care

    (2013)
  • H.M. Frost et al.

    The “muscle-bone unit” in children and adolescents: a 2000 overview

    J. Pediatr. Endocrinol. Metab.

    (2000)
  • G. Lombardi et al.

    Novel bone metabolism-associated hormones: the importance of the pre-analytical phase to for understanding their physiological roles

    Endocrine

    (2017)
  • Cited by (147)

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