Eavesdropping on Muscle-Bone Crosstalk
Safety Assessment
Susan Y. Smith

Eavesdropping on Muscle-Bone Crosstalk

Incredibly, musculoskeletal diseases are the most common cause of chronic disabilities worldwide(1), with costs greater than breast cancer, stroke, and cardiovascular disease combined. The loss of bone (osteoporosis) and muscle (sarcopenia) are two major disorders of aging and major contributors to frailty. We know that besides biomechanical function, skeletal muscle and bone are endocrine organs able to secrete factors capable of modulating biological function within their microenvironment, in nearby tissues, or in distant organs(2). Muscle and bone, the largest tissues in non-obese humans, share a close anatomical and functional relationship, with evidence showing crosstalk occurs even before birth in mammals, and continues throughout development, growth and aging. It is also important to understand that growth during infancy is different from growth during puberty, which in turn is distinct from what happens during aging(3).

Yet despite recognizing that this close relationship exists, it is still unclear how the endocrine properties of muscle and bone sense and transduce biomechanical signals such as loading, unloading or exercise, or systemic hormonal stimuli into biochemical signals. Recent research developments provide some insight into muscle-bone function(1). These include discovery of the involvement of clock genes as common muscle and bone promoters, the importance of the redox system in the etiology of insulin resistance, sarcopenia and osteoporosis (with mitochondrial function/dysfunction placed at the center of this theory), and the importance of cell mobility and role of factors involved in cell interaction such as Ephrins. Recognition of a role of muscle and bone in insulin resistance has enormous implications in view of the increasing incidence of obesity and diabetes, and the disability associated with metabolic syndrome.

The bone field has been successful in developing therapeutics for prevention or treatment of osteoporosis, but the development of therapeutics to treat sarcopenia have been delayed by lack of a clear definition of what the disease is, and what biomarkers and specific measures should be used(3). While measures of muscle mass are important and relevant, measures of functionality to assess physical performance may be more important to show that changes translate to improved muscle strength. Novel markers of sarcopenia, such as measures of mitochondrial activity and neuro-muscular activation, may play a key role and need to be validated, necessitating development of new technologies and animal models to study this area.

Joining forces

Combining the expertise from the bone and muscle fields to unravel the mechanisms underlying muscle-bone interaction may mean therapeutic options to treat osteoporosis and sarcopenia together may one day be possible(3) . There is a growing body of evidence that there are pleiotropic genes that play important roles in both tissues. Some circulating and local mediators have been identified that functionally couple muscle and bone, such as the growth hormone/insulin-like factor-1 (IGF-1) axis, and paracrine production of IGF-1 and FGF-23. In line with this, inhibition of myostatin, a myokine and muscle growth inhibitor thought to be produced specifically by myocytes, has also been shown to have beneficial effects on bone.

In addition to therapeutics, it is clear that exercise has beneficial effects on bone and muscle(3) although imposing an exercise regime on an aging population may not be practical. A recent study showed coupling exercise with energy restriction resulted in favourable changes in muscle mass and bone mineral density in the face of significant fat loss. Fat tissue and the nervous system clearly interact to affect both muscle and bone mass and function. The sympathetic nervous system plays an important role in the browning (conversion) of white fat to the more desirable brown fat. Irisin, a myokine induced during exercise, may enhance the generation of “beige” or brown-like adipocytes. So far, the effects of irisin on the skeleton have not been reported.

As we identify key players involved in muscle-bone crosstalk we can look forward to seeing how the important relationships between bone and muscle, and fat, unfold. Taken together, our current knowledge of muscle-bone interactions suggest we are on the verge of a new and exciting integrated area in the field of musculoskeletal research.

So chat away.


  1. Bonnet N. Meeting Report: Cutting edge discoveries in muscle biology, disease and therapeutics (ASBMR 2013). IBMS BoneKEy 11, Article number: 515 (2014) I doi: 10.1038/bonekey.2014.10; published online 19 February 2014 (www.nature.com/bonekey)
  2. Cianferotti L, Brandi ML. Review: Muscle-bone interactions: basic and clinical aspects. Endocrine 45: 165-177, 2014
  3. Bonewald LF, Kiel DP, Clemens TL, et al. Perspective: Forum on bone and skeletal muscle interaction: Summary of the proceedings of an ASBMR workshop. JBMR 28(9): 1857-1865, 2013