Interactions between Muscle and Bone-Where Physics Meets Biology

Abstract

Muscle and bone interact via physical forces and secreted osteokines and myokines. Physical forces are generated through gravity, locomotion, exercise, and external devices. Cells sense mechanical strain via adhesion molecules and translate it into biochemical responses, modulating the basic mechanisms of cellular biology such as lineage commitment, tissue formation, and maturation. This may result in the initiation of bone formation, muscle hypertrophy, and the enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements. Bone and muscle mass, resistance to strain, and the stiffness of matrix, cells, and tissues are enhanced, influencing fracture resistance and muscle power. This propagates a dynamic and continuous reciprocity of physicochemical interaction. Secreted growth and differentiation factors are important effectors of mutual interaction. The acute effects of exercise induce the secretion of exosomes with cargo molecules that are capable of mediating the endocrine effects between muscle, bone, and the organism. Long-term changes induce adaptations of the respective tissue secretome that maintain adequate homeostatic conditions. Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized while immobility and inflammation trigger muscle and bone marrow fatty infiltration and propagate degenerative diseases such as sarcopenia and osteoporosis. Ongoing research will certainly find new therapeutic targets for prevention and treatment.

Keywords: bone; mechanosensing; mechanotransduction; muscle; myokines; osteokines adaptation.

Figure 1

Schematic overview of the interaction between muscle and bone in physiology and pathology, addressing also the most important effectors of interaction. The green color represents the physiological interactions indicating that muscle hypertrophy and high bone mass have interdependent relationships, while the red color shows similarly strong mutual interaction between the loss of bone and muscle due to the intrinsic pathology in degenerative disease such as osteoporosis and sarcopenia, but also lifestyle, disuse, and underlying metabolic diseases such as chronic inflammatory conditions and diabetes mellitus.

Figure 2

Mechanisms of mechanotransduction. Graphical summary of the current knowledge on the transduction of mechanical signals into a cellular response. A) Mechanical strain applied to the cell and (the resulting) fluid flow activate receptors and channels and their downstream signaling cascades. In a tissue context, strain is transmitted between cells via a series of adhesion molecules such as integrins, cadherins, and tight junctions. Transcription factors become nucleotropic and address DNA regulatory elements such as repressors, enhancers, and their specific DNA response elements. Adaptive transcription and translation are initiated and lead to changes in transcriptome, proteome, and especially the secretome to communicate with neighbors and distant tissues. The expression and secretion of extracellular matrix proteins as parts of the secretome are upregulated. As a consequence, the incoming forces and the resistive response to external forces are enhanced, and a new homeostasis situation is produced. Similarly, the production of proteins of the cytoskeleton is enhanced, the cytoskeleton is also becoming stiffer, and the contractile proteins generate even more active forces. B) Fluid flow is sensed by the primary cilium. The relevant structural features of a primary cilium are schematically depicted on the right side, while the signaling cascades and tools for mechanotransduction are depicted on the left side. Deflection of the cilium generates signaling [43,44]. Intraflagellar transport is a means of active transport of signaling peptides to and from the cell body. C) The constitutive secretory pathway and the regulated secretory pathway are schematically depicted. While the latter has not been demonstrated in muscle or bone, it is characteristic for truly endocrine cells and requires complex sorting and the intravesicular storage of preformed proteins that are extruded upon endocrine signals. The constitutive pathway requires characteristic secretory peptide sequences to be continuously released into the extracellular environment and subsequently the circulation. The release of vesicles upon exercise-related calcium flux into the cell has been demonstrated to be a candidate mechanism for the release of proteins and miRNAs. Abbreviations: RTK: receptor tyrosine kinase; GPCR: G-protein coupled receptor; ATP: adenosine triphosphate; cAMP: cyclic adenosine-monophosphate; ECM: extracellular matrix; AKAPs: A-kinase anchoring proteins; PDEs: phosphodiesterases; P2X7R: purinergic receptor P2X, ligand-gated ion channel; TGN: trans-Golgi-network; This figures was created using inspiring information and cartoons from [6,9,40,44,45,46,47,48,49,50,51].

Figure 2

Mechanisms of mechanotransduction. Graphical summary of the current knowledge on the transduction of mechanical signals into a cellular response. A) Mechanical strain applied to the cell and (the resulting) fluid flow activate receptors and channels and their downstream signaling cascades. In a tissue context, strain is transmitted between cells via a series of adhesion molecules such as integrins, cadherins, and tight junctions. Transcription factors become nucleotropic and address DNA regulatory elements such as repressors, enhancers, and their specific DNA response elements. Adaptive transcription and translation are initiated and lead to changes in transcriptome, proteome, and especially the secretome to communicate with neighbors and distant tissues. The expression and secretion of extracellular matrix proteins as parts of the secretome are upregulated. As a consequence, the incoming forces and the resistive response to external forces are enhanced, and a new homeostasis situation is produced. Similarly, the production of proteins of the cytoskeleton is enhanced, the cytoskeleton is also becoming stiffer, and the contractile proteins generate even more active forces. B) Fluid flow is sensed by the primary cilium. The relevant structural features of a primary cilium are schematically depicted on the right side, while the signaling cascades and tools for mechanotransduction are depicted on the left side. Deflection of the cilium generates signaling [43,44]. Intraflagellar transport is a means of active transport of signaling peptides to and from the cell body. C) The constitutive secretory pathway and the regulated secretory pathway are schematically depicted. While the latter has not been demonstrated in muscle or bone, it is characteristic for truly endocrine cells and requires complex sorting and the intravesicular storage of preformed proteins that are extruded upon endocrine signals. The constitutive pathway requires characteristic secretory peptide sequences to be continuously released into the extracellular environment and subsequently the circulation. The release of vesicles upon exercise-related calcium flux into the cell has been demonstrated to be a candidate mechanism for the release of proteins and miRNAs. Abbreviations: RTK: receptor tyrosine kinase; GPCR: G-protein coupled receptor; ATP: adenosine triphosphate; cAMP: cyclic adenosine-monophosphate; ECM: extracellular matrix; AKAPs: A-kinase anchoring proteins; PDEs: phosphodiesterases; P2X7R: purinergic receptor P2X, ligand-gated ion channel; TGN: trans-Golgi-network; This figures was created using inspiring information and cartoons from [6,9,40,44,45,46,47,48,49,50,51].

Figure 3

Magnetic resonance imaging (MRI)-based muscle imaging. Weighted image of young healthy (top left) and elderly sarcopenic male (top right). Water fraction (bottom left) and fat fraction (bottom right) images of subject shown in top right.

Figure 4

Segmentation of MRI (magnetic resonance imaging) images. left: T1 image used for the segmentation of the fascia lata (red) separating the subcutaneous adipose tissue from the group of muscles and IMAT; center: Dixon fat fraction (FF) image with segmented: muscles (black) and IMAT (yellow and red), smaller agglomerations of extramyocellular lipids (EMCL) are shown in red; right: remaining muscle tissue for which FF is determined (Images from University of Erlangen).