Skeletal muscle Ca2+ mishandling: Another effect of bone-to-muscle signaling

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Abstract

Our appreciation of crosstalk between muscle and bone has recently expanded beyond mechanical force-driven events to encompass a variety of signaling factors originating in one tissue and communicating to the other. While the recent identification of new ‘myokines’ has shifted some focus to the role of muscle in this partnership, bone-derived factors and their effects on skeletal muscle should not be overlooked. This review summarizes some previously known mediators of bone-to-muscle signaling and also recent work identifying a new role for bone-derived TGF-β as a cause of skeletal muscle weakness in the setting of cancer-induced bone destruction. Oxidation of the ryanodine receptor/calcium release channel (RyR1) in skeletal muscle occurs via a TGF-β-Nox4-RyR1 axis and leads to calcium mishandling and decreased muscle function. Multiple points of potential therapeutic intervention were identified, from preventing the bone destruction to stabilizing the RYR1 calcium channel. This new data reinforces the concept that bone can be an important source of signaling factors in pathphysiological settings.

Introduction

Interactions between skeletal muscle and bone have long been considered primarily based on a simple mechanical understanding. Bone is shaped by mechanical force applied by muscles and gravity and bone provides an attachment site for muscle to maintain shape and drive locomotion. Recently, however, we have begun to understand an additional and more complex endocrine-based crosstalk between bone and muscle that goes beyond the mechanical connection. Given the close ties between bone and muscle, it is not surprising that development and maintenance of these two tissues are coordinated. Further, it would be expected that compromising either bone or muscle by disease, disuse/unloading or aging would affect both tissues. It is with this backdrop that we describe some previously-known bone-to-muscle signaling factors and then a newly identified cause of skeletal muscle weakness in osteolytic cancer in bone.

Section snippets

Developmental links between muscle and bone

Muscle and bone develop in close physical association and are interdependently regulated throughout development and adult life by mechanical strain, direct signaling crosstalk, and endocrine mechanisms. Physical factors such as exercise, aging, or disuse cause coordinated changes in bone and muscle mass in both experimental animal models and humans. While the anabolic effects of increased movement and loading and, conversely, the catabolic effects of immobilization or disuse have been

Bone-derived signals can affect muscle mass and function

Far from being a passive mineral storehouse, bone is increasingly recognized as an active signaling mediator and endocrine organ. Both osteoblasts and osteocytes secrete signaling molecules that can act in paracrine and endocrine fashions. Osteocalcin is a peptide secreted by osteoblasts that can signal to multiple cell types, including skeletal muscle, via the Gprc6a receptor. Osteocalcin production and activation in bone is increased in response to insulin signaling in osteoblasts.

Calcium handling in skeletal muscle

Proper calcium handling in muscle is critical for contraction. During excitation–contraction (E–C) coupling in skeletal muscle, sequestered calcium in the sarcoplasmic reticulum (SR) is released through activated ryanodine receptors (RyR1) into the cytoplasm, permitting calcium-dependent actin-myosin cross-bridging and muscle contraction [44]. Cytosolic calcium is then transferred back to the lumen of the SR via the calcium-ATPase pump (SERCA1) (Fig. 1). Maladaptive oxidative modifications of

Osteolytic cancer in bone and skeletal muscle weakness

Bone is a frequent site for cancer metastases, with more than 450,000 patients affected per year in the U.S. Osteolytic cancer in bone is a major contributor to decreased survival and quality of life for patients [50], [51]. Pathologic fractures caused by osteolytic cancer in bone in breast cancer patients increases risk of death compared to breast cancer patients without fractures [51]. Similarly, elevated serum bone resorption marker levels are highly predictive of negative outcomes in

Bone-derived TGF-β leads to skeletal muscle weakness via increase in oxidative stress

TGF-β has been implicated in muscle weakness [43] and TGF-β is released from bone as a consequence of bone metastases [60]. SMAD3 phosphorylation was increased in muscle of mice and humans with bone metastases, implicating TGF-β signaling in weakness. To investigate the contribution of this signaling pathway, we blocked TGF-β in mice with breast cancer bone metastases using: (1) TGF-β receptor I kinase inhibitor (SD-208) [64], (2) anti-TGF-β ligand monoclonal antibody (1D11), or (3)

Summary

Bone and muscle functions are tightly coupled in normal physiology. Recent studies have focused on muscle as an endocrine organ with a predominant role over bone in bone-muscle crosstalk. Osteolytic cancer in bone represents a divergence from normal bone physiology by tipping the balance of remodeling. Our recently published work shows the bone destruction driven by osteolytic tumor cells also directly causes skeletal muscle weakness. We have identified the TGF-β-Nox4-RyR1 axis as the mechanism

Conflict of interest statement

T.A.G. has been a consultant for Novartis.

No potential conflicts of interest were disclosed by J.N.R. or D.L.W.

Acknowledgements

This work was supported by NIH grants (U01CA143057 from the NCI Tumor Microenvironment Network; R01CA69158), Susan G. Komen Foundation, the Jerry and Peggy Throgmartin Endowment of the IU Simon Cancer Center, IU Simon Cancer Center Breast Cancer Program, American Cancer Society and IU Simon Cancer Center (IRG-84-002-28), the IU Health Strategic Research Initiative in Oncology, and a generous donation from the Withycombe family.

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