Interactions between Muscle and Bone—Where Physics Meets Biology

In the paper

“Many interactions are not only bilateral but follow a multilateral or even organismic relationship, involving metabolism and the nervous system (Figure 1).”

In the paper

“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.”

In the paper

“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.”

In the paper

“Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized”

In the paper

“Secreted growth and differentiation factors are important effectors of mutual interaction.”

In the paper

“Muscle and bone interact via physical forces and secreted osteokines and myokines.”

What the sources say

• Not checked yetcites [1] Felsenthal, 2017, Mechanical regulation of musculoskeletal system development, Dev. source
• Not checked yetcites [2] Mikolajewicz, 2019, Transmission of Mechanical Information by Purinergic Signaling, Biophys. J. source
• Not checked yetcites [3] Vogel, 2018, Unraveling the Mechanobiology of Extracellular Matrix, Annu. Rev. Physiol. source
• Not checked yetcites [4] Ayad, 2019, Tissue mechanics, an important regulator of development and disease, Philos. Trans. R. Soc. B: Boil. Sci. source

In the paper

“and propagate degenerative diseases such as sarcopenia and osteoporosis.”

In the paper

“Recent information indicates that the reciprocity of mechanochemical interaction is extremely dynamic, including the cellular, the tissue, and the organismic level [1,2,3,4].”

What the sources say

• Not checked yetcites [1] Felsenthal, 2017, Mechanical regulation of musculoskeletal system development, Dev. source
• Not checked yetcites [2] Mikolajewicz, 2019, Transmission of Mechanical Information by Purinergic Signaling, Biophys. J. source
• Not checked yetcites [3] Vogel, 2018, Unraveling the Mechanobiology of Extracellular Matrix, Annu. Rev. Physiol. source
• Not checked yetcites [4] Ayad, 2019, Tissue mechanics, an important regulator of development and disease, Philos. Trans. R. Soc. B: Boil. Sci. source

In the paper

“The physical forces generated in the context of motion are extremely variable from very low to high impact.”

In the paper

“Connective tissues physically joining muscle and bone, especially tendons and ligaments, naturally play a critical role in this interaction, as addressed in a recent review article in detail [5].”

What the sources say

• Not checked yetcites [5] Nassari, 2017, Non-myogenic Contribution to Muscle Development and Homeostasis: The Role of Connective Tissues, Front. Cell Dev. Boil.

In the paper

“The variability of impact on the different levels of cell/cell, cell/tissue, and tissue/tissue interaction ranges from 0.1 to 100 kPa from development to adult life”

What the sources say

• Not checked yetcites [3] Vogel, 2018, Unraveling the Mechanobiology of Extracellular Matrix, Annu. Rev. Physiol. source
• Not checked yetcites [6] Mohammed, 2019, Innovative Tools for Mechanobiology: Unraveling Outside-In and Inside-Out Mechanotransduction, Front. Bioeng. Biotechnol. source
• Not checked yetcites [7] Moro, 2019, MicroRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis, Nat.
• Not checked yetcites [8] Uroz, 2018, Regulation of cell cycle progression by cell–cell and cell–matrix forces, Nat.

In the paper

“Intrinsic as well as extrinsic forces such as gravity generate adaptive changes of tissues, which modulate muscle power and fracture resistance.”

In the paper

“Long-term changes induce adaptations of the respective tissue secretome that maintain adequate homeostatic conditions.”

In the paper

“Vibration certainly can also elicit cellular responses, which may be beneficial in terms of inducing and maintaining muscle hypertrophy and elevated bone mass under conditions of disuse or unloading in simulated microgravity [12,13,14].”

What the sources say

• Not checked yetcites [12] Pagnotti, 2019, Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity, Nat. Rev. Endocrinol. source
• Not checked yetcites [13] Stolzenberg, 2013, Whole-body vibration versus proprioceptive training on postural control in post-menopausal osteopenic women, Gait Posture source
• Not checked yetcites [14] Blottner, 2006, Human skeletal muscle structure and function preserved by vibration muscle exercise following 55 days of bed rest, Graefe’s Arch. Clin. Exp. Ophthalmol.

In the paper

“In response to forces, all cells and tissues adapt their resistive forces as mediated through the strength and stiffness of their cytoskeleton and extracellular matrix (ECM).”

In the paper

“For the time being, it is probably correct to state that vibration techniques if correctly applied may help to delay disuse-related and microgravity-related muscle and bone loss”

In the paper

“Moreover, the weight-saving mode of construction of bone architecture allows for local adaptations to the directions of incoming forces (force lines); these are phenomena that for bone have been described earlier as Wolff’s law, in which form follows function [10,11].”

What the sources say

• Not checked yetcites [10] Duncan, 1995, Transduction of mechanical strain in bone, ASGSB Bull. Publ. Am. Soc. Gravit. Space Boil.
• Not checked yetcites [11] Duncan, 1995, Mechanotransduction and the functional response of bone to mechanical strain, Calcif. Tissue Int. source

In the paper

“and produces a complex interactive network of physics and biochemistry involving both muscle and bone [3,6,7,8].”

What the sources say

• Not checked yetcites [3] Vogel, 2018, Unraveling the Mechanobiology of Extracellular Matrix, Annu. Rev. Physiol. source
• Not checked yetcites [6] Mohammed, 2019, Innovative Tools for Mechanobiology: Unraveling Outside-In and Inside-Out Mechanotransduction, Front. Bioeng. Biotechnol. source
• Not checked yetcites [7] Moro, 2019, MicroRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis, Nat.
• Not checked yetcites [8] Uroz, 2018, Regulation of cell cycle progression by cell–cell and cell–matrix forces, Nat.

In the paper

“Cellular deformations induce adaptive signaling that provides adequate function, fulfilling the actual environmental needs/challenges. [22,23,24,25,26].”

What the sources say

• Not checked yetcites [22] Alfieri, 2019, Flow-induced mechanotransduction in skeletal cells, Biophys. Rev. source
• Not checked yetcites [23] Quiroga, 2019, The plasma membrane as a mechanochemical transducer, Philos. Trans. R. Soc. B: Boil. Sci. source
• Not checked yetcites [24] Lemke, 2017, Mechanical forces during muscle development, Mech. Dev. source
• Not checked yetcites [25] Sun, 2019, Integrin activation by talin, kindlin and mechanical forces, Nat.
• Not checked yetcites [26] Sun, 2016, Integrin-mediated mechanotransduction, J. Cell Boil. source

In the paper

“Many molecular mechanisms of mechanosensing and mechanotransduction are common pathways for muscle and bone.”

What the sources say

• Not checked yetcites [32] Jin, 2019, Physicochemical Niche Conditions and Mechanosensing by Osteocytes and Myocytes, Curr. Osteoporos. Rep. source
• Not checked yetcites [33] Hinton, 2018, In Vivo Osteocyte Mechanotransduction: Recent Developments and Future Directions, Curr. Osteoporos. Rep. source

In the paper

“The last three decades have seen an emancipation of mechanobiology as a modulator of cellular biochemistry, which is highly relevant for tissue formation already early in development and throughout the adult life cycle for tissue maintenance, remodeling, and regeneration [1,19].”

What the sources say

• Not checked yetcites [1] Felsenthal, 2017, Mechanical regulation of musculoskeletal system development, Dev. source
• Not checked yetcites [19] Iskratsch, 2014, Appreciating force and shape — the rise of mechanotransduction in cell biology, Nat. Rev. Mol. Cell Boil. source

In the paper

“Mechanical stimulation enhances calcium flux into the cell (reviewed in [22])”

What the sources say

• Not checked yetcites [22] Alfieri, 2019, Flow-induced mechanotransduction in skeletal cells, Biophys. Rev. source

In the paper

“Connexin 43 has functions beyond the physical mechanotransduction between cells, since its knockout in early osteoblasts causes impaired muscle formation in mice [28,29].”

What the sources say

• Not checked yetcites [28] Plotkin, 2017, Connexins and Pannexins in Bone and Skeletal Muscle, Curr. Osteoporos. Rep. source
• Not checked yetcites [29] Shen, 2015, Deletion of connexin43 in osteoblasts/osteocytes leads to impaired muscle formation in mice, J. Bone Miner. Res. source

In the paper

“Integrin-mediated mechanotransduction is but one of many molecular mechanisms that appear to be linked to successful muscle regeneration in health, aging, and disease [27].”

What the sources say

• Not checked yetcites [27] Rozo, 2016, Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice, Nat. Med. source

In the paper

“Physical forces through muscular activity or vibration induce the cellular secretion of ATP and sphingosines, which are tightly involved in osteoblast, osteoclast, and osteocyte activity [2,63,64,65].”

What the sources say

• Not checked yetcites [2] Mikolajewicz, 2019, Transmission of Mechanical Information by Purinergic Signaling, Biophys. J. source
• Not checked yetcites [63] Formigli, 2009, Regulation of transient receptor potential canonical channel 1 (TRPC1) by sphingosine 1-phosphate in C2C12 myoblasts and its relevance for a role of mechanotransduction in skeletal muscle differentiation, J. Cell Sci. source
• Not checked yetcites [64] Brotto, 2015, Bone and muscle: Interactions beyond mechanical, Bone source
• Not checked yetcites [65] Sassoli, C., Pierucci, F., Zecchi-Orlandini, S., and Meacci, E. (2019). Sphingosine 1-Phosphate (S1P)/ S1P Receptor Signaling and Mechanotransduction: Implications for Intrinsic Tissue Repair/Regeneration. Int. J. Mol. Sci., 20. source

In the paper

“Transcription activation is also variably dependent on the amplitude, frequency, and duration of mechanical stimuli [52,54].”

What the sources say

• Not checked yetcites [52] Seefried, 2017, Dissection of mechanoresponse elements in promoter sites of the mechanoresponsive CYR61 gene, Exp. Cell Res. source
• Not checked yetcites [54] Seefried, 2017, Epidermal growth factor as a mechanosensitizer in human bone marrow stromal cells, Stem Cell Res. source

In the paper

“Moreover, the sensitivity to mechanical signals in bone is of course strongly modulated by other signaling molecules, as it was for example shown for estrogens and the mechano-related effects on fracture healing [15,17].”

What the sources say

• Not checked yetcites [15] Lackner, 2018, Effects of low-magnitude high-frequency vibration on osteoblasts are dependent on estrogen receptor α signaling and cytoskeletal remodeling, Biochem. Biophys. Res. Commun. source
• Not checked yetcites [17] Wehrle, 2014, The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice, Dis. Model. Mech.

In the paper

“There is no evidence that mesenchymal tissues express the tools for classical regulated secretion”

What the sources say

• Not checked yetcites [66] Furber, K.L., Backlund, P.S., Yergey, A.L., and Coorssen, J.R. (2019). Unbiased Thiol-Labeling and Top-Down Proteomic Analyses Implicate Multiple Proteins in the Late Steps of Regulated Secretion. Proteomes, 7. source
• Not checked yetcites [67] Gerber, 2002, Molecular determinants of regulated exocytosis, Diabetes source
• Not checked yetcites [68] Park, 2008, How peptide hormone vesicles are transported to the secretion site for exocytosis, Mol. Endocrinol. source
• Not checked yetcites [69] Takamori, 2006, Molecular Anatomy of a Trafficking Organelle, Cell source

In the paper

“since the inhibition of flagellar transport 88 protein abolished this osteogenic response [22].”

What the sources say

• Not checked yetcites [22] Alfieri, 2019, Flow-induced mechanotransduction in skeletal cells, Biophys. Rev. source

In the paper

“and the resulting calcium spikes may well be the adequate stimulus for the secretion of extracellular vesicles upon exercise as a basis for exercise-induced tissue cross-talk”

In the paper

“It is rather its indirect effect via rickets-associated myopathy that influences muscle mass and function, while its direct effects on muscle cell proliferation, differentiation, and contractility may be neglectable [83,84].”

What the sources say

• Not checked yetcites [83] Avin, 2018, Fibroblast growth factor 23 does not directly influence skeletal muscle cell proliferation and differentiation or ex vivo muscle contractility, Am. J. Physiol. Metab.
• Not checked yetcites [84] Edmonston, 2019, FGF23 at the crossroads of phosphate, iron economy and erythropoiesis, Nat. Rev. Nephrol. source

In the paper

“indicating the putative in vivo relevance of vesicle-related information exchange between muscle and bone [74,75].”

What the sources say

• Not checked yetcites [74] Trovato, 2019, Extracellular Vesicles: Delivery Vehicles of Myokines, Front. Physiol. source
• Not checked yetcites [75] Annibalini, 2019, Muscle and Systemic Molecular Responses to a Single Flywheel Based Iso-Inertial Training Session in Resistance-Trained Men, Front. Physiol. source

In the paper

“Recent evidence links high SOST serum levels in Korean sarcopenic women with appendicular skeletal muscle mass [77].”

What the sources say

• Not checked yetcites [77] Kim, 2019, Association of serum sclerostin levels with low skeletal muscle mass: The Korean Sarcopenic Obesity Study (KSOS), Bone source

In the paper

“an in vitro study showed that osteocyte calcium oscillation as stimulated by mechanical loading induced the release of LAMP1 (lysosomal-associated membrane protein 1) containing EVs that regulate bone formation and mineralization [72].”

What the sources say

• Not checked yetcites [72] Morrell, 2018, Mechanically induced Ca2+ oscillations in osteocytes release extracellular vesicles and enhance bone formation, Bone Res. source

In the paper

“Annibalini et al. analyzed the serum content of microvesicles in subjects ahead and 2 h after exercise and found a 2-fold increase in microvesicles of around 80–200 nm in size”

What the sources say

• Not checked yetcites [74] Trovato, 2019, Extracellular Vesicles: Delivery Vehicles of Myokines, Front. Physiol. source
• Not checked yetcites [75] Annibalini, 2019, Muscle and Systemic Molecular Responses to a Single Flywheel Based Iso-Inertial Training Session in Resistance-Trained Men, Front. Physiol. source

In the paper

“The study showed that it bypasses this pathway”

What the sources say

• Not checked yetcites [85] Yamamoto, 2015, Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition, Bone source

In the paper

“The injection of uncarboxylated osteocalcin in mice rescued their exercise capacity and rescued the age-associated loss of muscle mass (reviewed in [76].”

What the sources say

• Not checked yetcites [76] Moser, S.C., and Van Der Eerden, B. (2019). Osteocalcin—A Versatile Bone-Derived Hormone. Front. Endocrinol., 9. source

In the paper

“there is high plausibility that these precursors can give rise to any mesenchyme-derived tissue type including e.g., bone, cartilage, muscle, tendon, ligament, and fat tissue [98,99,100].”

What the sources say

• Not checked yetcites [98] Herrmann, 2019, Bone Marrow Niches for Skeletal Progenitor Cells and their Inhabitants in Health and Disease, Curr. Stem Cell Res. Ther. source
• Not checked yetcites [99] Robey, 2017, “Mesenchymal stem cells”: Fact or fiction, and implications in their therapeutic use, F1000Research source
• Not checked yetcites [100] Sacchetti, 2016, No Identical “Mesenchymal Stem Cells” at Different Times and Sites: Human Committed Progenitors of Distinct Origin and Differentiation Potential Are Incorporated as Adventitial Cells in Microvessels, Stem Cell Rep. source

In the paper

“After 12 weeks of exercise, the same type of exercise bout induces a list of genes where collagens and remodeling-associated genes such as lysyl oxidase homolog 2 precursor (LOXL2), matrix-remodeling associated 5, and thrombospondin-4 (TSP-4) prevail, indicating constant ECM remodeling.”

What the sources say

• Not checked yetcites [62] Pourteymour, 2017, Global mRNA sequencing of human skeletal muscle: Search for novel exercise-regulated myokines, Mol. Metab. source

In the paper

“Principal signaling cascades of bone formation involve canonical and non-canonical Wnt signaling, the TGFβ receptor family, and its various ligands (above all BMPs), and the parathyroid hormone receptor (PTH1R) [111].”

What the sources say

• Not checked yetcites [111] Baron, 2013, WNT signaling in bone homeostasis and disease: from human mutations to treatments, Nat. Med. source

In the paper

“already very early in in skeletal development, there is evidence for an important role of mechanical forces in addition to other physical cues and soluble morphogens in controlling cellular fate determinations, patterning, and tissue development [45,46,110].”

What the sources say

• Not checked yetcites [45] Mammoto, 2013, Mechanobiology and Developmental Control, Annu. Rev. Cell Dev. Boil. source
• Not checked yetcites [46] Arvind, 2017, Mechanobiology of limb musculoskeletal development, Ann. New York Acad. Sci. source
• Not checked yetcites [110] Sharir, 2011, Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis, Dev. source

In the paper

“There is evidence from genome-wide association studies that pleiotropic genes may both regulate bone and muscle homoeostasis as recently reviewed [59].”

What the sources say

• Not checked yetcites [59] Bonewald, 2019, Use it or lose it to age: A review of bone and muscle communication, Bone source

In the paper

“Three main pathways of protein secretion by muscle cells could be identified, namely (1) conventional secretion, (2) secretion via nanovesicles with typical exosomal features, and (3) larger microvesicles (up to 200 nm in size) with distinct protein and mRNA cargo [89]”

What the sources say

• Not checked yetcites [89] Bigot, 2012, In-depth analysis of the secretome identifies three major independent secretory pathways in differentiating human myoblasts, J. Proteom. source

In the paper

“Next to mechanical stimuli, early bone regeneration is also associated with the secretion of proinflammatory factors showing again many parallels to the muscle regeneration mechanisms discussed below. It is supported by a proinflammatory reaction initiated by platelets in case of injury (platelet-derived growth factor (PDGF) and cytokine signaling) and/or by TLR 2 and 4 and their ligands such as S”

What the sources say

• Not checked yetcites [91] Ebert, 2015, Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells, Stem Cell Res. source
• Not checked yetcites [122] Recknagel, 2012, Fracture healing under healthy and inflammatory conditions, Nat. Rev. Rheumatol. source
• Not checked yetcites [123] Einhorn, 2014, Fracture healing: Mechanisms and interventions, Nat. Rev. Rheumatol. source
• Not checked yetcites [124] Rauner, 2012, WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production, J. Bone Miner. Res. source

In the paper

“Notch signaling is also a crucial pathway for postnatal muscle regeneration.”

What the sources say

• Not checked yetcites [131] Baghdadi, 2018, Regulation and phylogeny of skeletal muscle regeneration, Dev. Boil. source
• Not checked yetcites [134] Mourikis, 2019, Notch signalling: Sensor and instructor of the microenvironment to coordinate cell fate and organ morphogenesis, Curr. Opin. Cell Boil. source

In the paper

“Bone remodeling involves the removal of gratuitous or old and damaged bone by osteoclasts ahead of tissue restoration according to (new) physical strain conditions [118].”

What the sources say

• Not checked yetcites [118] Ma, 2019, The role of physical forces in osteoclastogenesis, J. Cell. Physiol. source

In the paper

“Osteoclast activation responds to physical strain via the osteocyte receptor activator of NF-κB ligand (RANKL) production in order to restore localized microstructural heterogeneities caused by aging or new lines of forces that generate regions of “micro-unloading” [121].”

What the sources say

• Not checked yetcites [121] Paul, 2018, Mechanical Stimuli in the Local In Vivo Environment in Bone: Computational Approaches Linking Organ-Scale Loads to Cellular Signals, Curr. Osteoporos. Rep. source

In the paper

“Analogous to our findings in skeletal precursors, mechanically induced Notch signaling is involved in a protein network that regulates myostatin expression in the context of cytoskeletal rearrangements via integrin-mediated AKT/PKB and mTORC1 signaling [58,135].”

What the sources say

• Not checked yetcites [58] Ziouti, F., Ebert, R., Rummler, M., Krug, M., Müller-Deubert, S., Lüdemann, M., Jakob, F., Willie, B.M., and Jundt, F. (2019). NOTCH Signaling Is Activated through Mechanical Strain in Human Bone Marrow-Derived Mesenchymal Stromal Cells. Stem Cells Int., 2019. source
• Not checked yetcites [135] Rindom, 2016, Mechanosensitive Molecular Networks Involved in Transducing Resistance Exercise-Signals into Muscle Protein Accretion, Front. Physiol. source

In the paper

“Satellite cells, located between the basement membrane and plasmalemma of the muscle fiber, are the principal muscle stem cells that organize muscle regeneration after injury.”

What the sources say

• Not checked yetcites [131] Baghdadi, 2018, Regulation and phylogeny of skeletal muscle regeneration, Dev. Boil. source

In the paper

“Among others, slit guidance ligand 3 (SLIT3) usherin, Fraser syndrome 1 (Fras-1), atrial natriuretic peptide, afamin, collagen α-1 chain, laminin β2, angiotensin-converting enzyme, and ADAMTS-like protein 4 were identified in a screen as osteoclast-derived compounds that stimulate osteoblast activity.”

What the sources say

• Not checked yetcites [119] Kim, 2018, Coupling factors involved in preserving bone balance, Cell. Mol. Life Sci. source

In the paper

“The orchestrating network transcription factor is paired box gene 3 (Pax3), which is the core transcription factor that initiates myogenic signaling through the family of myogenic regulatory factors (MRF), which includes MyoD, myogenin, Myf5, and MRF4.”

What the sources say

• Not checked yetcites [128] Buckingham, 2017, Gene regulatory networks and cell lineages that underlie the formation of skeletal muscle, Proc. Natl. Acad. Sci. source
• Not checked yetcites [129] Chal, 2017, Making muscle: Skeletal myogenesisin vivoandin vitro, Dev. source
• Not checked yetcites [130] Xu, 2019, Regulation of skeletal myogenesis by microRNAs, J. Cell. Physiol. source

In the paper

“systems such as sphingosine 1-phosphate and its receptor appear to be involved in mechanotransduction not only in development but also in adult life [65,120].”

What the sources say

• Not checked yetcites [65] Sassoli, C., Pierucci, F., Zecchi-Orlandini, S., and Meacci, E. (2019). Sphingosine 1-Phosphate (S1P)/ S1P Receptor Signaling and Mechanotransduction: Implications for Intrinsic Tissue Repair/Regeneration. Int. J. Mol. Sci., 20. source
• Not checked yetcites [120] Alto, 2017, Semaphorins and their Signaling Mechanisms, Breast Cancer

In the paper

“Intriguingly, the vitamin D receptor (VDR), an important steroid hormone receptor in both muscle and bone, also fundamentally changes DNA architecture via CTCF interaction [155,156].”

What the sources say

• Not checked yetcites [155] Carlberg, C. (2018). Vitamin D Genomics: From In Vitro to In Vivo. Front. Endocrinol., 9. source
• Not checked yetcites [156] Carlberg, 2018, In vivo response of the human epigenome to vitamin D: A Proof-of-principle study, J. Steroid Biochem. Mol. Boil. source

In the paper

“Cells of both the innate and the adaptive immune system are intricately involved in the efficient regeneration in both muscle and bone [93,137].”

What the sources say

• Not checked yetcites [93] Sass, F.A., Fuchs, M., Pumberger, M., Geissler, S., Duda, G.N., Perka, C., and Schmidt-Bleek, K. (2018). Immunology Guides Skeletal Muscle Regeneration. Int. J. Mol. Sci., 19. source
• Not checked yetcites [137] Chen, 2019, The role of satellite and other functional cell types in muscle repair and regeneration, J. Muscle Res. Cell Motil. source

In the paper

“Long-term bed-rest µG simulation over 90 days 6° head-down tilt was followed by a decrease of a muscle fiber cross-sectional area of 26% [167].”

What the sources say

• Not checked yetcites [167] Rittweger, 2005, Muscle atrophy and bone loss after 90 days’ bed rest and the effects of flywheel resistive exercise and pamidronate: Results from the LTBR study, Bone source

In the paper

“This TF can obviously change nuclear architecture to dominantly set up the muscle cell differentiation program even in a preformed environment through cooperation with the architectural protein CTCF (CCCTC-binding factor) [154].”

What the sources say

• Not checked yetcites [154] Sartorelli, 2018, Shaping Gene Expression by Landscaping Chromatin Architecture: Lessons from a Master, Mol. Cell source

In the paper

“Moreover, the local delivery of VDR ligands via vitamin D metabolizing enzymes is influenced by power exercise in a rat model, providing very strong links between muscle and bone interaction and epigenetics [157].”

What the sources say

• Not checked yetcites [157] Buskermolen, 2019, Effects of different training modalities on phosphate homeostasis and local vitamin D metabolism in rat bone, PeerJ source

In the paper

“Finally, macrophages are remarkably influenced by physical cues, including oxygen and physical forces, as to their phenotype and function, rendering them important players in the interaction of muscle and bone [140].”

What the sources say

• Not checked yetcites [140] Jain, 2019, Mechanobiology of Macrophages: How Physical Factors Coregulate Macrophage Plasticity and Phagocytosis, Annu. Rev. Biomed. Eng. source

In the paper

“Endothelial cells (EC) are essential for tissue regeneration.”

What the sources say

• Not checked yetcites [146] Chen, 2016, Endothelial cells are progenitors of cardiac pericytes and vascular smooth muscle cells, Nat. Commun. source
• Not checked yetcites [147] Chopra, 2018, Insights into Endothelial Progenitor Cells: Origin, Classification, Potentials, and Prospects, Stem Cells Int. source
• Not checked yetcites [148] Kusumbe, 2014, Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone, Nat. source
• Not checked yetcites [149] Ramasamy, 2014, Endothelial Notch activity promotes angiogenesis and osteogenesis in bone, Nat. source
• Not checked yetcites [150] Sivaraj, 2016, Blood vessel formation and function in bone, Dev. source

In the paper

“Careful studies on the molecular mechanisms revealed that the majority of regulated genes and proteins were related to insulin resistance, metabolism, and reduced protein synthesis [170,171,172].”

What the sources say

• Not checked yetcites [170] Gao, Y., Arfat, Y., Wang, H., and Goswami, N. (2018). Muscle Atrophy Induced by Mechanical Unloading: Mechanisms and Potential Countermeasures. Front. Physiol., 9. source
• Not checked yetcites [171] Salanova, 2014, Disuse deterioration of human skeletal muscle challenged by resistive exercise superimposed with vibration: evidence from structural and proteomic analysis, FASEB J. source
• Not checked yetcites [172] Salanova, 2015, Vibration mechanosignals superimposed to resistive exercise result in baseline skeletal muscle transcriptome profiles following chronic disuse in bed rest, Sci. Rep. source

In the paper

“A series of carefully designed studies on the effects of serum biomarkers for muscle and bone turnover regulation has been conducted, which confirmed that a continuous loss of both muscle and bone mass could be observed during simulated µG.”

What the sources say

• Not checked yetcites [167] Rittweger, 2005, Muscle atrophy and bone loss after 90 days’ bed rest and the effects of flywheel resistive exercise and pamidronate: Results from the LTBR study, Bone source

In the paper

“Yet, the unloading of muscle and skeleton causes muscle wasting and bone loss even in younger subjects.”

What the sources say

• Not checked yetcites [12] Pagnotti, 2019, Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity, Nat. Rev. Endocrinol. source
• Not checked yetcites [165] Koedijk, 2017, Sedentary behaviour and bone health in children, adolescents and young adults: a systematic review-supplementary presentation, Osteoporos. Int. source

In the paper

“Intra- and extramyocellular lipids, IMCL and smaller EMCL agglomerations, are not captured by IMAT as measured by MRI (Figure 4).”

In the paper

“For example, in muscle, FF reflects all EMCL and IMCL.”

In the paper

“With MR Dixon sequences that generate so-called fat and water fraction images (Figure 3 bottom) [182], the fat fraction which is the combined %fat of the analyzed VOI and can be quantified.”

What the sources say

• Not checked yetcites [182] Grimm, 2018, Repeatability of Dixon magnetic resonance imaging and magnetic resonance spectroscopy for quantitative muscle fat assessments in the thigh, J. Cachex- Sarcopenia Muscle source

In the paper

“Exercise and mechanotransduction can be a countermeasure for this type of chronic inflammatory tissue degeneration.”

In the paper

“However, there is a disassociation between muscle strength or power and lean mass or muscle size with respect to exercise intervention and age-dependent changes, because the contractile muscle capacity is strongly influenced by the EMCL and IMCL distribution [190,191,192,193,194].”

What the sources say

• Not checked yetcites [190] Addison, 2014, Intramuscular fat and inflammation differ in older adults: the impact of frailty and inactivity, J. Nutr. Heal. Aging source
• Not checked yetcites [191] Addison, 2014, Intermuscular Fat: A Review of the Consequences and Causes, Int. J. Endocrinol. source
• Not checked yetcites [192] Loenneke, 2019, Exercise-Induced Changes in Muscle Size do not Contribute to Exercise-Induced Changes in Muscle Strength, Sports Med. source
• Not checked yetcites [193] Morales, 2017, Muscle Lipid Metabolism: Role of Lipid Droplets and Perilipins, J. Diabetes Res. source
• Not checked yetcites [194] Tieland, 2017, Skeletal muscle performance and ageing, J. Cachex- Sarcopenia Muscle source

In the paper

“Computed tomography is an alternative 3D modality for muscle imaging [185].”

What the sources say

• Not checked yetcites [185] Engelke, 2018, Quantitative analysis of skeletal muscle by computed tomography imaging-State of the art, J. Orthop. Transl.

In the paper

“Spaceflight observations are proof of principle test conditions for Zero-G, and such reports confirm the rapid loss of muscle volume and all types of muscle fibers even in short-term spaceflights already after a short time in space of 5–111 days (reviewed in [170].”

What the sources say

• Not checked yetcites [170] Gao, Y., Arfat, Y., Wang, H., and Goswami, N. (2018). Muscle Atrophy Induced by Mechanical Unloading: Mechanisms and Potential Countermeasures. Front. Physiol., 9. source

In the paper

“Apart from chronic inflammatory rheumatic and intestinal diseases, so-called subclinical inflammation is also a driver of tissue-related “inflammaging”.”

What the sources say

• Not checked yetcites [91] Ebert, 2015, Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells, Stem Cell Res. source
• Not checked yetcites [107] Gilbert, 2019, The consequences of ageing, progeroid syndromes and cellular senescence on mechanotransduction and the nucleus, Exp. Cell Res. source
• Not checked yetcites [108] Serrano, 2014, Cellular senescence: from physiology to pathology, Nat. Rev. Mol. Cell Boil. source
• Not checked yetcites [109] Czarkwiani, 2018, Out with the old, in with the new: senescence in development, Curr. Opin. Cell Boil. source
• Not checked yetcites [177] Schell, 2011, Inflammatory phase of bone healing initiates the regenerative healing cascade, Cell Tissue Research

In the paper

“Differentiation between these components is only possible with MR spectroscopy (MRS) [183,184], which is not an imaging method.”

What the sources say

• Not checked yetcites [183] Xiao, 2011, Diffusion-weighted magnetic resonance spectroscopy: A novel approach to investigate intramyocellular lipids, Magn. Reson. Med. source
• Not checked yetcites [184] Boesch, 1997, In vivo determination of intra-myocellular lipids in human muscle by means of localized 1H-MR-spectroscopy, Magn. Reson. Med. source

In the paper

“In men, a decrease in subcutaneous fat thickness increased hip fracture risk independent of area bone mineral density (BMD) [196], but in women, independent contributions of DXA fat or lean measurements on fracture risk could not be shown so far [197,198,199].”

What the sources say

• Not checked yetcites [197] McLean, 2018, Lower Lean Mass Measured by Dual-Energy X-ray Absorptiometry (DXA) is Not Associated with Increased Risk of Hip Fracture in Women: The Framingham Osteoporosis Study, Calcif. Tissue Int. source
• Not checked yetcites [198] Schott, 1998, How Hip and Whole-Body Bone Mineral Density Predict Hip Fracture in Elderly Women: The EPIDOS Prospective Study, Osteoporos. Int. source
• Not checked yetcites [199] Zaslavsky, 2016, Association between body composition and hip fractures in older women with physical frailty, Geriatr. Gerontol. Int. source

In the paper

“Decreasing physical input leads to muscle atrophy and bone loss, as is most impressively documented under zero-G in space missions.”

In the paper

“Muscle and bone interact in order to provide adaptive modeling and remodeling mechanisms in an environment that is physically challenging.”

In the paper

“In men, a decrease in subcutaneous fat thickness increased hip fracture risk independent of area bone mineral density (BMD) [196], but in women, independent contributions of DXA fat or lean measurements on fracture risk could not be shown so far [197,198,199].”

What the sources say

• Not checked yetcites [196] Malkov, 2015, Hip Fractures Risk in Older Men and Women Associated With DXA-Derived Measures of Thigh Subcutaneous Fat Thickness, Cross-Sectional Muscle Area, and Muscle Density, J. Bone Miner. Res. source