CoChat
Sign Up
Cited by 197Muscle Physiology and DisordersBone health and osteoporosis researchSpaceflight effects on biology

Interactions between Muscle and Bone—Where Physics Meets Biology

Open access
Herrmann, Marietta, Engelke, Klaus, Ebert, Regina, Müller-Deubert, Sigrid, Rudert, Maximilian, Ziouti, Fani, Jundt, Franziska, Felsenberg, Dieter +1 more·2020·Biomolecules
DOI 10.3390/biom10030432PMC PMC7175139
Open this paper in CoChat — free accountOpen PDF

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.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes how muscle and bone communicate through mechanical forces and secreted factors, integrating mechanobiology with endocrine/paracrine signaling. It argues that loading maintains musculoskeletal homeostasis while unloading and chronic inflammation drive fatty infiltration and degenerative diseases such as sarcopenia and osteoporosis.

Key findings

  • Mechanical impacts ranging from 0.1 to 100 kPa are sensed by adhesion molecules, ion channels, the primary cilium, and other mechanotransduction machinery, leading to bone formation, muscle hypertrophy, and enhanced ECM/cytoskeletal stiffness, fracture resistance, and muscle power.
  • Muscle and bone act as endocrine organs via myokines/osteokines and extracellular vesicles; exosomes are 50–150 nm and microvesicles 50–1000 nm (up to 10 µm), carrying miRNA, proteins, and organelles that may mediate exercise-induced cross-talk.
  • Unloading causes rapid loss: a meta-analysis of 75 simulated microgravity studies found moderate muscle changes within 7–14 days and large effects on muscle force, mass, and peak power after 35 days; 90-day 6° head-down tilt bed rest decreased muscle fiber cross-sectional area by 26%, with increased SOST and myostatin that was reversible upon reloading.
  • Chronic inflammation and disuse promote muscle fatty infiltration and bone marrow adipose expansion; in the EFFECT study of 40 female acute hip fracture patients and 55 controls, soft tissue parameters discriminated hip fractures as well as trabecular BMD plus cortical thickness.

Methods

  • Narrative review; no primary experimental data are reported. It synthesizes mechanistic, developmental, clinical, imaging, and spaceflight/bed-rest literature.
  • Cites specific studies and meta-analyses, including 75 simulated microgravity studies, a 90-day bed-rest study, the EFFECT cross-sectional study of 40 female hip fracture patients and 55 controls, and imaging methods such as DXA, BIA, CT, MRI/Dixon, and MRS.
  • Main analysis is conceptual integration of mechanotransduction, secretome/extracellular vesicle biology, immune and endothelial interactions, epigenetics, and disease mechanisms.

Limitations

  • The paper states that more research is needed to dissect molecular events, define the borders between beneficial and harmful mechanical stimuli, and understand exercise resistance in disease; it also says it cannot provide an in-depth review of any pathology.
  • Evident from the text: as a narrative review, no systematic search strategy or risk-of-bias assessment is described, and conclusions rely on selected cited literature rather than new data.
  • Evident from the text: many mechanistic claims derive from mouse or in vitro studies and are not fully validated in humans; imaging lacks guidelines for which parameters to quantify, and direct comparison of CT muscle density with MRI Dixon fat fraction has not been published.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/biom10030432

Cites

205 of 205 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 204 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Many interactions between muscle and bone are not only bilateral but follow multilateral or even organismic relationship, involving metabolism and nervous system.

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

    Acute effects of exercise induce secretion of exosomes with cargo molecules capable of mediating endocrine effects between muscle, bone, and organism.

    “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.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Cells sense mechanical strain via adhesion molecules and translate it into biochemical responses, modulating lineage commitment, tissue formation, and maturation.

    “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.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Unloading, microgravity, and disuse cause removal or reorganization of gratuitous tissue.

    “Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Secreted growth and differentiation factors are important effectors of mutual interaction between muscle and bone.

    “Secreted growth and differentiation factors are important effectors of mutual interaction.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 59
  • Classified as probably not a substantial claim. 15
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingcitation

    In a retrospective analysis of the European Femur Fracture Study (EFFECT), after adjustment for BMD and cortical thickness, the hip fracture group was characterized by lower relative adipose tissue volume of the upper thigh and some texture parameters discriminated osteoporotic hip fracture.

    “After adjustment for BMD and cortical thickness, the hip fracture group was characterized by the lower relative adipose tissue volume of the upper thigh and some of the texture parameters discriminated the osteoporotic hip fracture [204].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [204] Museyko, 2019, Three-dimensional Distribution of Muscle and Adipose Tissue of the Thigh at CT: Association with Acute Hip Fracture, Radiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Physical forces are generated through gravity, locomotion, exercise, and external devices.

    “Physical forces are generated through gravity, locomotion, exercise, and external devices.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Mechanical strain can initiate bone formation, muscle hypertrophy, and enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements.

    “This may result in the initiation of bone formation, muscle hypertrophy, and the enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Immobility and inflammation trigger muscle and bone marrow fatty infiltration.

    “immobility and inflammation trigger muscle and bone marrow fatty infiltration”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Bone and muscle mass, resistance to strain, and stiffness of matrix, cells, and tissues are enhanced by physical impact, influencing fracture resistance and muscle power.

    “Bone and muscle mass, resistance to strain, and the stiffness of matrix, cells, and tissues are enhanced, influencing fracture resistance and muscle power.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Deformation prevails in muscle while bone strongly (but not exclusively) responds to fluid flow in osteocyte canalicular network.

    “The former prevail in muscle while bone strongly (but not exclusively) responds to fluid flow in the osteocyte canalicular network [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Nachury, 2019, Establishing and regulating the composition of cilia for signal transduction, Nat. Rev. Mol. Cell Boil. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Virtually every step of cell and tissue biology depends upon mechanochemical events.

    ““virtually every step of cell and tissue biology depends upon mechanochemical events””
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Storm, 2017, Mechanoreciprocity in cell migration, Nat.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Clinical result of physical impact is high bone and muscle mass, resulting in enhanced fracture resistance and muscle power.

    “The clinical result of physical impact is high bone and muscle mass, resulting in enhanced fracture resistance and muscle power (see also Figure 2A,B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Mechanical stimuli can be transmitted through deformation (stretching and compression) and/or shear strain applied by fluids that pass by.

    “Mechanical stimuli can be transmitted through deformation (stretching and compression) and/or shear strain applied by fluids that pass by.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    External mechanical vibration may variably substitute for gravity and add up to active muscle contraction both in space missions and as dedicated types of exercise.

    “There is no doubt that external mechanical vibration may variably substitute for gravity and add up to active muscle contraction both in space missions and as dedicated types of exercise.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In human myoblasts, Cav3 deficiency is associated with hyperactivation of IL-6-STAT3 signaling, which in presence of WT Cav3 is regulated by mechanical strain in a Cav3-dependent manner.

    “In human myoblasts, Cav3 deficiency was associated with the hyperactivation of IL-6-STAT3 signaling (interleukin-6, signal transducer and activator of transcription 3), which is a pathway that in the presence of WT Cav3 turned out to be regulated by mechanical strain in a Cav3-dependent manner [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Dewulf, 2019, Dystrophy-associated caveolin-3 mutations reveal that caveolae couple IL6/STAT3 signaling with mechanosensing in human muscle cells, Nat. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mechanical bending/deflection of cilium enhances PTGS2/COX2 expression and prostaglandin production as well as BMP2 and osteopontin expression.

    “Mechanical bending/deflection of the cilium was reported to enhance prostaglandin-endoperoxide synthase 2 (PTGS2 alias COX2) expression and prostaglandin production as well as bone morphogenetic protein 2 (BMP 2) and osteopontin expression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Secreted proteins and signaling molecules are basis of mutual interaction between muscle and bone both in paracrine and endocrine setting.

    “Secreted proteins and signaling molecules are the basis of mutual interaction between muscle and bone both in a paracrine and also an endocrine setting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In muscle, mechanosensing is mainly transduced via deformation strains, but primary cilium has been related to satellite cell self-renewal and muscle cell differentiation in mice.

    “In muscle, mechanosensing is mainly transduced via deformation strains, but still, the primary cilium has been related to satellite cell self-renewal and muscle cell differentiation in mice [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Marican, 2016, Asymmetric Distribution of Primary Cilia Allocates Satellite Cells for Self-Renewal, Stem Cell Rep. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Primary cilium is a unique subcellular organelle composed of nine (+0) axonema structures.

    “The primary cilium is a unique subcellular organelle composed of nine (+0) axonema structures (Figure 2B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    In bone, primary cilium appears to be important mediator of gravity and consecutive osteogenic response, because in simulated microgravity, cilium gradually shrinks and inhibition of this shrinkage using cytochalasin D maintains osteoblast differentiation capacity.

    “In bone, the primary cilium appears to be an important mediator of gravity and consecutive osteogenic response, because in simulated microgravity, the cilium gradually shrinks and inhibition of this shrinkage using cytochalasin D maintains osteoblast differentiation capacity (reviewed in [40]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Shi, 2019, Novel functions of the primary cilium in bone disease and cancer, Cytoskelet. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    IGF-1 and FGF2 are growth factors actively secreted at muscle and bone interface and if delivered into circulation may have distant effects on bone formation and remodeling.

    “IGF-1 and also FGF2 are growth factors that are actively secreted at the muscle and bone interface and if delivered into the circulation may have distant effects on bone formation and remodeling.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    EVs may transport myokines/osteokines, miRNA, and organelles and are involved in regeneration of both bone and muscle tissue after exercise and injury.

    “EVs may transport myokines/osteokines, miRNA, and organelles and are involved in the regeneration of both bone and muscle tissue after exercise and injury [70,71,72,73,74].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [70] Bittel, 2019, Contribution of Extracellular Vesicles in Rebuilding Injured Muscles, Front. Physiol. source

      Not checked in the free run.

    • cites [71] Lauritzen, 2013, Contraction and AICAR Stimulate IL-6 Vesicle Depletion From Skeletal Muscle Fibers In Vivo, Diabetes source

      Not checked in the free run.

    • cites [72] Morrell, 2018, Mechanically induced Ca2+ oscillations in osteocytes release extracellular vesicles and enhance bone formation, Bone Res. source

      Not checked in the free run.

    • cites [73] Murray, 2018, Concise Review: Intercellular Communication Via Organelle Transfer in the Biology and Therapeutic Applications of Stem Cells, STEM CELLS source

      Not checked in the free run.

    • cites [74] Trovato, 2019, Extracellular Vesicles: Delivery Vehicles of Myokines, Front. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle cells, very much like bone, do not express molecular components of RSP, and vesicle release upon exercise may be relevant mechanism to deliver IL-6 into circulation.

    “Muscle cells, very much like bone, do not express the molecular components of the regulated secretory pathway (RSP), and the vesicle release upon exercise may be the relevant mechanism to deliver IL-6 into the circulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Exercise downregulates both SOST and DKK-1 serum levels, marking an important link between muscle and bone via physical impact.

    “Exercise was reported to downregulate both SOST and DKK-1 serum levels, which marks an important link between muscle and bone via physical impact [78,79].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] Davoodi, 2019, Improved carotid intima-media thickness-induced high-intensity interval training associated with decreased serum levels of Dkk-1 and sclerostin in type 2 diabetes, J. Diabetes its Complicat.

      Not checked in the free run.

    • cites [79] Picke, 2018, Differential effects of high-fat diet and exercise training on bone and energy metabolism, Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immediate rise of muscle IGF-1 mRNA after exercise bout and significant rise of peripheral blood IGF-1 protein levels after 24 h (not yet significant after 2 h) post exercise, which was gone after 48 h.

    “One example is the immediate rise of muscle insulin-like growth factor 1 (IGF-1) mRNA after an exercise bout and the significant rise of peripheral blood IGF-1 protein levels after 24 h (not yet significant after 2 h) post exercise, which was gone after 48 h [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Annibalini, 2019, Muscle and Systemic Molecular Responses to a Single Flywheel Based Iso-Inertial Training Session in Resistance-Trained Men, Front. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Small vesicles in muscle contain immunoreactive IL-6 and are depleted during exercise in mice.

    “Small vesicles in muscle, which contain immunoreactive IL-6 and are depleted during exercise, have indeed been described in mice [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Lauritzen, 2013, Contraction and AICAR Stimulate IL-6 Vesicle Depletion From Skeletal Muscle Fibers In Vivo, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Hippo pathway is an important pathway in mechanotransduction and skeletal physiology, and downstream YAP/TAZ regulation is tightly involved in mechanosensing and mechanotransduction in bone, muscle, and other cells, especially endothelial cells.

    “Similarly, the Hippo pathway has gained attention as an important pathway in mechanotransduction and skeletal physiology. Downstream YAP/TAZ regulation is in fact tightly involved in mechanosensing and mechanotransduction both in bone and muscle as well as in many other cells, especially endothelial cells (see Section 3.3).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [55] Dasgupta, 2019, Control of cellular responses to mechanical cues through YAP/TAZ regulation, J. Boil. Chem. source

      Not checked in the free run.

    • cites [115] Meng, 2018, RAP2 mediates mechanoresponses of the Hippo pathway, Nat. source

      Not checked in the free run.

    • cites [116] Xiang, 2018, The versatile hippo pathway in oral-maxillofacial development and bone remodeling, Dev. Boil. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    During development, the interaction between physics and biology is boosted by EMT and the acquisition of migratory capacity, and every step of interaction causes and supports biological consequences in terms of lineage commitment and maturation.

    “In conclusion, there is convincing evidence that during development, the interaction between physics and biology is boosted by EMT and the acquisition of migratory capacity, and every step of interaction causes and supports biological consequences in terms of lineage commitment and maturation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Irisin, a cleaved product of FNDC5 with stimulating effects on bone formation, is delivered from muscle into circulation after exercise but may have dual mode of delivery, shedding of preformed polypeptides and de novo synthesis.

    “Irisin, a cleaved product of fibronectin type III domain containing (FNDC5) with stimulating effects on bone formation, is also delivered from muscle into the circulation after exercise but may have a dual mode of delivery, shedding of preformed polypeptides and de novo synthesis [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Li, 2019, Muscle-bone crosstalk and potential therapies for sarco-osteoporosis, J. Cell. Biochem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PTH1R signaling cascade is especially sensitive to mechanical loading, and anabolic PTH1R signals elicited through intermittent 1-34 PTH (teriparatide) are almost ineffective under conditions of unloading.

    “Above all, the PTH1R signaling cascade is especially sensitive to mechanical loading. Anabolic PTH1R signals elicited through bone anabolic treatment using intermittent 1-34 PTH (teriparatide) are almost ineffective under conditions of unloading [113].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Tu, 2016, Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor, J. Bone Miner. Res.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TSP-4 is expressed in muscle and bone, has different functions compared to TSP-1 (antiangiogenic), and has been assigned to angiogenesis and matrix remodeling.

    “TSP-4 is expressed in muscle and bone, has different functions compared to TSP-1 (antiangiogenic), and recently has been assigned to angiogenesis and matrix remodeling [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Stenina-Adognravi, O., and Plow, E.F. (2019). Thrombospondin-4 in tissue remodeling. Matrix Boil., 300–313. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Joint structures develop under the influence of core signaling cascades of osteogenic, chondrogenic, and ligamentogenic pathways, and this process is fundamentally influenced by mechanical forces already in utero, directed by fetal movement.

    “Joint structures as important features of the musculoskeletal functional unit develop under the influence of respective core signaling cascades of osteogenic, chondrogenic, and ligamentogenic pathways. This process is fundamentally influenced by mechanical forces already in utero, directed by movement of the fetus [45,101].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Mammoto, 2013, Mechanobiology and Developmental Control, Annu. Rev. Cell Dev. Boil. source

      Not checked in the free run.

    • cites [101] Chijimatsu, 2019, Mechanisms of synovial joint and articular cartilage development, Cell. Mol. Life Sci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There are genes whose expression is relevant for tissue formation in both bone and muscle, and others cause antagonistic effects in the brother tissues.

    “These data demonstrate that there are genes whose expression is relevant for tissue formation in both bone and muscle, and others cause antagonistic effects in the brother tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Notch signaling is involved in skeletal physiology and is mechanosensitive in skeletal precursors.

    “Notch signaling has also been reported to be involved in skeletal physiology. We and others recently reported that this pathway is mechanosensitive in skeletal precursors [58,114].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [114] Canalis, 2018, Notch in skeletal physiology and disease, Osteoporos. Int. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Early exercise-induced genes such as proinflammatory cytokines IL-1b, IL-6, IL-8, TLR4 ligands SAA1 and SAA2, CYR61/CCN1, CTGF/CCN2, ANGPTL4, and ANGPTL2 closely resemble genes relevant in the initial phase of osteogenic differentiation and contribute to angiogenesis in fracture healing.

    “Interestingly, the early genes such as proinflammatory cytokines IL-1b, IL-6, IL-8, the toll-like receptor 4 (TLR4) ligands serum amyloid A1 (SAA1) and SAA2, CYR61/CCN1, connective tissue growth factor (CTGF/CCN2), angiopoietin-like 4 (ANGPTL4) and ANGPTL2 very closely resemble genes that are also relevant in the initial phase of osteogenic differentiation and contribute to angiogenesis in fract”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [92] Loi, 2016, Inflammation, fracture and bone repair, Bone source

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    The lists of muscle-related transcripts and secreted proteins comprised 149 proteins of unassigned functions as putative interactors with other tissues and 123 transcripts corresponding to putative myokines including BMPs, chemokines, cytokines, GDFs, TNF family members, and Wnt ligands.

    “The lists of muscle-related transcripts and secreted proteins comprised 149 proteins of unassigned functions as putative interactors with other tissues and 123 transcripts that corresponded to putative myokines including BMPs, chemokines, cytokines, growth/differentiation factors (GDFs), and members of the tumor necrosis factor (TNF) family of secreted proteins and ligands for Wnt signaling (Suppl”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Zhang, 2018, Transcriptional profiling reveals extraordinary diversity among skeletal muscle tissues, eLife source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bone formation and bone resorption are both part of adaptive refinement and remodeling processes, which are mechanically guided and where both osteoblasts and osteoclasts respond to physical forces.

    “Bone formation and bone resorption are both part of the adaptive refinement and remodeling processes, which are mechanically guided and where both osteoblasts and osteoclasts respond to physical forces [117,118].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Amarasekara, D.S., Yun, H., Kim, S., Lee, N., Kim, H., and Rho, J. (2018). Regulation of Osteoclast Differentiation by Cytokine Networks. Immune Netw., 18. source

      Not checked in the free run.

    • cites [118] Ma, 2019, The role of physical forces in osteoclastogenesis, J. Cell. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fibro-adipogenic progenitors (FAPs) residing in the muscle interstitium substantially contribute to regeneration by supporting the amplification and fusion of satellite cells, and pharmacological inhibition of FAPs impairs regeneration efficiency.

    “However, there are some other populations that substantially contribute to regeneration such as the Sca1+/CD34+ fibro-adipogenic progenitors (FAPs) residing in the muscle interstitium. Following injury, satellite cells re-enter the cell cycle and proliferate to give rise to myoblasts that differentiate and fuse to restore the damaged fiber or generate myofibers de novo, while FAPs support their”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Baghdadi, 2018, Regulation and phylogeny of skeletal muscle regeneration, Dev. Boil. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The initial phase of muscle regeneration is governed by intrinsic inflammatory signals and is further induced by innate immune cells such as sequentially recruited neutrophils and resident macrophages; IL-1, IL-6, and IL-8 are involved in innate immune cell recruitment until IL-10 and TGFβ1 introduce the anti-inflammatory phase.

    “Very much in analogy with bone and probably many other tissues, the initial phase of regeneration is governed by intrinsic inflammatory signals and is further induced by cells of the innate immune system, e.g. sequentially recruited neutrophils and resident macrophages. Cytokines already known from bone regeneration such as IL-1, 6, and 8 are involved in innate immune cell recruitment until the”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [132] Dort, J., Fabre, P., Molina, T., and Dumont, N.A. (2019). Macrophages Are Key Regulators of Stem Cells during Skeletal Muscle Regeneration and Diseases. Stem Cells Int., 2019. source

      Not checked in the free run.

    • cites [133] Mukund, 2019, Skeletal muscle: A review of molecular structure and function, in health and disease, Wiley Interdiscip. Rev. Syst. Boil. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both Pax7-deficient and satellite cell-deficient mice fail to regenerate muscle.

    “Both Pax7-deficient and satellite cell-deficient mice fail to regenerate muscle [131].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Baghdadi, 2018, Regulation and phylogeny of skeletal muscle regeneration, Dev. Boil. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The early proinflammatory condition in regenerating tissues mimics the senescence-associated secretory phenotype (SASP); it appears beneficial if intermittent but causes pathology if chronically active.

    “Not only is this condition in common for regenerating tissues in the early phase, but it also somehow mimics the senescence-associated secretory phenotype (SASP) of presenescent and senescent cells. It appears to be beneficial if intermittent, but it causes pathology if chronically active.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [109] Czarkwiani, 2018, Out with the old, in with the new: senescence in development, Curr. Opin. Cell Boil. source

      Not checked in the free run.

    • cites [125] Farr, 2019, Cellular senescence in bone, Bone source

      Not checked in the free run.

    • cites [126] He, 2017, Senescence in Health and Disease, Cell source

      Not checked in the free run.

    • cites [127] Rhinn, 2019, Cellular senescence in development, regeneration and disease, Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Satellite stem cell development, in addition to Pax3 expression, is largely dependent on Pax7 expression in the pre- and perinatal periods and is modulated by mechanical strain.

    “Satellite stem cell development in addition to Pax3 expression is largely dependent on the expression of Pax7 in the pre- and perinatal periods and modulated by mechanical strain [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Jin, 2019, Physicochemical Niche Conditions and Mechanosensing by Osteocytes and Myocytes, Curr. Osteoporos. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In age-related osteoporosis, there are no significant associations to epigenetic marks or aging-associated DNA signatures in peripheral blood mononuclear cells, while others claim to see such associations, and the debate is ongoing.

    “In case of bone, we and others have recently reported that there are no significant associations to epigenetic marks or aging associated DNA signatures in peripheral blood mononuclear cells in age-related osteoporosis, while others claim to see such associations, and the debate is ongoing [159,160,161].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [159] Riancho, 2018, Epigenetics of Skeletal Diseases, Curr. Osteoporos. Rep. source

      Not checked in the free run.

    • cites [160] Eipel, 2017, Primary Osteoporosis Is Not Reflected by Disease-Specific DNA Methylation or Accelerated Epigenetic Age in Blood, J. Bone Miner. Res.

      Not checked in the free run.

    • cites [161] Jakob, 2018, Response to Letter to the Editor: Epigenetic Aging in Osteoporosis, J. Bone Miner. Res. source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    There are basically two systems to mutually communicate between muscle and bone where physics and biochemistry meet: physical forces exerted by physical load, muscle activity, and fluid flow are translated into biochemical signals, the primary biological response changes the receiving system so that the secondary response is different until homeostasis is achieved, while decreasing physical挑战

    “In conclusion, there are basically two systems to mutually communicate between muscle and bone where physics and biochemistry meet. Physical forces exerted by physical load, muscle activity (contraction and relaxation), and fluid flow are translated into biochemical signals and the biology of cells and tissues. The primary biological response to physical cues changes the receiving biological”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Muscle satellite cells attract and cross-talk with endothelial cells via vascular endothelial growth factor (VEGF) secretion, while the endothelial cell-derived Notch ligand Dll4 causes muscle stem cell quiescence and creates a vascular niche.

    “muscle satellite cells attract and cross-talk with EC via vascular endothelial growth factor (VEGF) secretion, while the EC-derived Notch ligand Dll4 causes muscle stem cell quiescence and creates a vascular niche [151].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Verma, 2018, Muscle Satellite Cell Cross-Talk with a Vascular Niche Maintains Quiescence via VEGF and Notch Signaling, Cell Stem Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The most obvious mechanisms that trigger diseases in both muscle and bone compartments are unloading and chronic inflammation.

    “When focusing on muscle and bone, the most obvious mechanisms that trigger diseases in both compartments are unloading and chronic inflammation, which will be discussed in the following sections for translational perspectives.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Macrophage PPARγ expression controls the delivery of growth differentiation factor-3 (GDF3) and is almost essential for muscle regeneration.

    “In addition, evidence showed that macrophage PPARƴ (peroxisome proliferator-activated receptor γ) expression controls the delivery of growth differentiation factor-3 (GDF3) and is almost essential for muscle regeneration [139].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Varga, 2016, Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration, Immun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial specification strongly contributes to bone microarchitectural structures such as cortical versus trabecular bone, and the process of endothelium specification and its mutual interaction with osteogenesis is Notch dependent.

    “For bone, it has been demonstrated that endothelial specification strongly contributes to microarchitectural structures—for example, cortical versus trabecular bone. Moreover, there is again an important contribution of Notch signaling since the process of endothelium specification and its mutual interaction with osteogenesis is Notch dependent [146,147,148,149,150].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [146] Chen, 2016, Endothelial cells are progenitors of cardiac pericytes and vascular smooth muscle cells, Nat. Commun. source

      Not checked in the free run.

    • cites [147] Chopra, 2018, Insights into Endothelial Progenitor Cells: Origin, Classification, Potentials, and Prospects, Stem Cells Int. source

      Not checked in the free run.

    • cites [148] Kusumbe, 2014, Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone, Nat. source

      Not checked in the free run.

    • cites [149] Ramasamy, 2014, Endothelial Notch activity promotes angiogenesis and osteogenesis in bone, Nat. source

      Not checked in the free run.

    • cites [150] Sivaraj, 2016, Blood vessel formation and function in bone, Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise is followed by epigenetic changes that modulate the accessibility of chromatin regions for adaptive signaling and determine the availability of metabolic intermediates for acetylation and methylation, and many of these effects remain as signatures that may even have a transgenerational impact.

    “With respect to exercise as a countermeasure of bone and muscle loss, there is evidence that exercise is followed by epigenetic changes that besides modulating the accessibility of chromatin regions for adaptive signaling even determine the availability of metabolic intermediates for acetylation and methylation. Moreover, many of these epigenetic effects remain as signatures that may even have a”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Axsom, 2019, Impact of parental exercise on epigenetic modifications inherited by offspring: A systematic review, Physiol. Rep. source

      Not checked in the free run.

    • cites [164] McGee, 2019, Epigenetics and Exercise, Trends Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial cells strongly respond to mechanical cues, and one important target for their mechanoresponse is the Notch pathway.

    “EC do strongly respond to mechanical cues, and one important target for their mechanoresponse is again the Notch pathway [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Mack, 2018, NOTCH regulation of the endothelial cell phenotype, Curr. Opin. Hematol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Skeletal precursors obtained from the bone marrow of osteoporotic patients harbor an almost diagnostic signature of their transcriptome, while the putatively epigenetic hubs of regulation await further identification.

    “What appears to be quite obvious is that skeletal precursors obtained from the bone marrow of osteoporotic patients harbor an almost diagnostic signature of their transcriptome, while the putatively epigenetic hubs of regulation await further identification [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Benisch, P., Schilling, T., Klein-Hitpass, L., Frey, S.P., Seefried, L., Raaijmakers, N., Krug, M., Regensburger, M., Zeck, S., and Schinke, T. (2012). The Transcriptional Profile of Mesenchymal Stem Cell Populations in Primary Osteoporosis Is Distinct and Shows Overexpression of Osteogenic Inhibitors. PLOS ONE, 7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of 75 μG simulation studies reported moderate changes on muscle parameters within 7-14 days of μG and large effects on muscle force, mass, and peak power after 35 days.

    “A recently published meta-analysis including 75 µG simulation studies reported moderate changes on muscle parameters within 7–14 days of µG and large effects on muscle force, mass, and peak power after 35 days [166].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Winnard, 2019, Effect of Time on Human Muscle Outcomes During Simulated Microgravity Exposure Without Countermeasures—Systematic Review, Front. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Tissue regeneration appears to be a teamwork that requires the interactions of several cell populations including tissue-specific precursors, immune cells, and endothelial precursors, whereby the latter also seem to be tissue specific, and this applies to both muscle and bone.

    “Overall, tissue regeneration appears to be a teamwork that requires the interactions of several cell populations including tissue-specific precursors, immune cells, and endothelial precursors, whereby also the latter seem to be tissue specific, and this applies to both muscle and bone [153].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Wosczyna, 2018, A Muscle Stem Cell Support Group: Coordinated Cellular Responses in Muscle Regeneration, Dev. Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Muscle regeneration starts with an inflammatory reaction that activates the myofiber-specific amplification and differentiation process and ends up in tissue remodeling according to mechanical challenge.

    “Overall, very much in analogy to bone regeneration, also muscle regeneration starts with an inflammatory reaction that activates the myofiber-specific amplification and differentiation process and ends up in tissue remodeling according to mechanical challenge.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Restorative macrophages orchestrate the interaction between myogenic cells and endothelial precursors during muscle regeneration via apelin (APLN), oncostatin M (OSM), and periostin (POSTN), which are also important for bone regeneration.

    “Restorative macrophages even orchestrate the interaction between myogenic cells and endothelial precursors during muscle regeneration. Interestingly, the main signaling molecules involved were apelin (APLN), oncostatin M (OSM), and periostin (POSTN), which are also important for bone regeneration [138].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Latroche, 2017, Coupling between Myogenesis and Angiogenesis during Skeletal Muscle Regeneration Is Stimulated by Restorative Macrophages, Stem Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    None of the modalities can actually measure muscle mass, but lean mass and muscle volume are used as surrogates.

    “None of the modalities can actually measure muscle mass, but lean mass and muscle volume are used as surrogates.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    BIA systems estimate fat and fat-free mass from electrical impedance measurements of trunk, arms, and legs using age, gender, and ethnic-specific algorithms validated in previous studies, albeit with large prediction errors for individuals.

    “Bioimpedance analysis systems estimate fat and fat-free mass from the electrical impedance measurements of trunk, arms, and legs using age, gender, and ethnic-specific algorithms validated in previous studies, albeit with large prediction errors for individuals [180].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Kyle, 2004, Bioelectrical impedance analysis?part I: review of principles and methods, Clin. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammation and disuse propagate muscle fatty infiltration and bone marrow adipose expansion, which contributes to inflammatory activity initiating a vicious cycle.

    “Inflammation and disuse also propagate muscle fatty infiltration and bone marrow adipose expansion, which even more contributes to inflammatory activity initiating a vicious cycle.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [107] Gilbert, 2019, The consequences of ageing, progeroid syndromes and cellular senescence on mechanotransduction and the nucleus, Exp. Cell Res. source

      Not checked in the free run.

    • cites [108] Serrano, 2014, Cellular senescence: from physiology to pathology, Nat. Rev. Mol. Cell Boil. source

      Not checked in the free run.

    • cites [109] Czarkwiani, 2018, Out with the old, in with the new: senescence in development, Curr. Opin. Cell Boil. source

      Not checked in the free run.

    • cites [177] Schell, 2011, Inflammatory phase of bone healing initiates the regenerative healing cascade, Cell Tissue Research

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    T1 images are used for the assessment of intermuscular adipose tissue (IMAT), which is the ensemble of 'white voxels' within the fascia lata.

    “T1 images are used for the assessment of intermuscular adipose tissue (IMAT), which is the ensemble of ‘white voxels’ within the fascia lata (FL) [181].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Karampinos, 2011, Characterization of the regional distribution of skeletal muscle adipose tissue in type 2 diabetes using chemical shift-based water/fat separation, J. Magn. Reson. Imaging source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Neither DXA nor BIA can provide three-dimensional measurements.

    “Neither DXA nor BIA can provide three-dimensional (3D) measurements.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Premisecitation

    AMPK, which functions as a main signal transduction mechanism for muscle hypertrophy, was identified in studies of molecular mechanisms of simulated μG.

    “As expected, the adenosine monophosphate-activated protein kinase (AMPK) that functions as a main signal transduction mechanism for muscle hypertrophy was identified [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Vilchinskaya, N.A., Krivoi, I.I., and Shenkman, B.S. (2018). AMP-Activated Protein Kinase as a Key Trigger for the Disuse-Induced Skeletal Muscle Remodeling. Int. J. Mol. Sci., 19. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DXA provides a quantitative measurement of lean (but not muscle) mass and of fat mass of the total body or a subpart.

    “The former provides a quantitative measurement of lean (but not of muscle) mass and of fat mass of the total body or a sub part of it (Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Buckinx, 2018, Pitfalls in the measurement of muscle mass: a need for a reference standard, J. Cachex- Sarcopenia Muscle source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Failure of timely resolution of inflammation through anti-inflammatory cytokines is key for roadblocks to tissue regeneration and drives aging and manifestations of SASP.

    “While inflammation is an essential part of the initial phase of tissue regeneration, the failure of timely resolution through anti-inflammatory cytokines is key for these roadblocks and it also drives aging and the manifestations of an inflammatory senescence-associated phenotype (SASP) [91,107,108,109,177].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [107] Gilbert, 2019, The consequences of ageing, progeroid syndromes and cellular senescence on mechanotransduction and the nucleus, Exp. Cell Res. source

      Not checked in the free run.

    • cites [108] Serrano, 2014, Cellular senescence: from physiology to pathology, Nat. Rev. Mol. Cell Boil. source

      Not checked in the free run.

    • cites [109] Czarkwiani, 2018, Out with the old, in with the new: senescence in development, Curr. Opin. Cell Boil. source

      Not checked in the free run.

    • cites [177] Schell, 2011, Inflammatory phase of bone healing initiates the regenerative healing cascade, Cell Tissue Research

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    With CT, muscle density measured in Hounsfield units can be quantified.

    “In analogy to Dixon imaging, with CT, a muscle density measured in Hounsfield units (HU) (0 HU for water and–1000 HU for air) can be quantified.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The value of muscle tissue (about 50-60 HU) is lowered by the infiltration of lipids.

    “The value of muscle tissue (about 50–60 HU) is lowered by the infiltration of lipids.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    In clinical routine, the preferred method is semi-quantitative assessment of muscle and adipose tissue area or volume from T1 weighted MR images, which show very good contrast between these two tissues.

    “In clinical routine, the preferred method is semi-quantitative assessment of muscle and adipose tissue area or volume from T1 weighted MR images, which show very good contrast between these two tissues (see Figure 3 top left and top right showing T1 weighted images from a young healthy normal male and from an elderly male with sarcopenia).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Chronic inflammation impairs mechanotransduction and triggers production of inhibitors of regeneration in muscle and bone, namely myostatin, activin, SOST, and DKK-1 under various clinical conditions.

    “It impairs mechanotransduction and triggers the production of inhibitors of regeneration in both compartments, namely myostatin, activin, SOST, and DKK-1 under various clinical conditions.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [107] Gilbert, 2019, The consequences of ageing, progeroid syndromes and cellular senescence on mechanotransduction and the nucleus, Exp. Cell Res. source

      Not checked in the free run.

    • cites [108] Serrano, 2014, Cellular senescence: from physiology to pathology, Nat. Rev. Mol. Cell Boil. source

      Not checked in the free run.

    • cites [109] Czarkwiani, 2018, Out with the old, in with the new: senescence in development, Curr. Opin. Cell Boil. source

      Not checked in the free run.

    • cites [177] Schell, 2011, Inflammatory phase of bone healing initiates the regenerative healing cascade, Cell Tissue Research

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic inflammation can be both a cause and consequence of disuse and atrophy in muscle and bone.

    “Chronic inflammation can be both a cause and consequence of disuse and atrophy in muscle and bone.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [107] Gilbert, 2019, The consequences of ageing, progeroid syndromes and cellular senescence on mechanotransduction and the nucleus, Exp. Cell Res. source

      Not checked in the free run.

    • cites [108] Serrano, 2014, Cellular senescence: from physiology to pathology, Nat. Rev. Mol. Cell Boil. source

      Not checked in the free run.

    • cites [109] Czarkwiani, 2018, Out with the old, in with the new: senescence in development, Curr. Opin. Cell Boil. source

      Not checked in the free run.

    • cites [177] Schell, 2011, Inflammatory phase of bone healing initiates the regenerative healing cascade, Cell Tissue Research

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both muscle and bone sense mechanical strain, transduce biochemical signals in response, and mutually influence the respective tissue architecture to balance muscle power and fracture resistance.

    “Both tissues sense mechanical strain, transduce biochemical signals in response, and mutually influence the respective tissue architecture to balance muscle power and fracture resistance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Epigenetics is strongly involved in aging phenomena, and recent research indicates that both positive exercise and training effects and also exercise resistance and degeneration can be modulated by epigenetic mechanisms.

    “Epigenetics is strongly involved in aging phenomena, and recent research indicates that both positive exercise and training effects and also exercise resistance and degeneration can be modulated by epigenetic mechanisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Continuous adaptive remodeling appears to be the key to delay aging-associated degeneration; hence, exercise and locomotion in concerted interaction between muscle and bone are core phenomena of health maintenance in higher organisms.

    “Continuous adaptive remodeling appears to be the key to delay aging-associated degeneration; hence, exercise and locomotion in concerted interaction between muscle and bone are core phenomena of health maintenance in higher organisms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The combination of soft tissue parameters discriminated hip fractures as well as a combination of trabecular BMD and cortical thickness, documenting a strong interaction between muscle and bone structure using fatty infiltration and other soft tissue architectural parameters as surrogate parameters.

    “Interestingly, the combination of soft tissue parameters discriminated hip fractures as well as a combination of trabecular BMD and cortical thickness, documenting a strong interaction between muscle and bone structure using fatty infiltration and other soft tissue architectural parameters as surrogate parameters.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Physical strain is transformed into a multitude of biochemical signals that causes modeling or remodeling until a new state of homeostasis is reached as long as the physical input remains in a steady state.

    “Physical strain is transformed into a multitude of biochemical signals that causes modeling or remodeling until a new state of homeostasis is reached as long as the physical input remains in a steady state.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Physical strain strongly modulates the biology of cells along their lineage commitment and maturation as well as the hypertrophy versus atrophy of tissues according to physical challenge.

    “It is physical strain that strongly modulates the biology of cells along their lineage commitment and maturation as well as the hypertrophy versus atrophy of tissues according to physical challenge.”
    Quote in the paperNot a substantial claim
70 of 70

  • The paper relies on this without support.

    Muscle and bone are derived from common precursors during development.

    “Muscle and bone are derived from common precursors during development, indicating a close relationship and interaction.”

  • The paper relies on this without support.

    There are currently no guidelines by which imaging parameter(s) should be quantified to address a given muscle composition question.

    “Currently, there are no guidelines by which imaging parameter(s) should be quantified to address a given muscle composition question.”

  • The paper relies on this without support.

    Comparative studies on imaging parameters for muscle composition are still missing.

    “Comparative studies are still missing.”

  • The paper relies on this without support.

    A direct comparison of CT muscle density with MRI Dixon FF results has not been published.

    “Interestingly, to the best of our knowledge, a direct comparison of CT muscle density with MRI Dixon FF results has not been published so far.”

  • The paper relies on this without support.

    The borders to pathology, which stimulus hurts cells, and which one stimulates adaptive remodeling are not yet exactly known.

    “We are beginning to understand the mechanisms of regulation, but we do not yet exactly know where the borders to pathology begin, which stimulus hurts cells, and which one stimulates adaptive remodeling.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The principal products secreted from bone that influence the formation, maintenance and regeneration of muscle are osteocalcin, FGF23, and sclerostin.

    “The principal products secreted from bone that influence the formation, maintenance and regeneration of muscle are the osteocalcin, a marker protein of osteoblasts, and FGF23, a phosphatonin derived from osteocytes, as well as the inhibitors of the osteogenic wingless (Wnt) signaling pathway, sclerostin [136].”

    From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [136]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Terry et al. publication year conflicts with the reference list

    Minor

    The text says the work by both Le Bihan et al. and Terry et al. was published in 2012, but reference 90 lists the Terry et al. paper as published in 2018.

1 of 1

Cites

Flagged first, then by citations

12 of the 217 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Herrmann, M., Engelke, K., Ebert, R., Müller-Deubert, S., Rudert, M., Ziouti, F., Jundt, F., Felsenberg, D., & Jakob, F.
Affiliations
  • University of Würzburg (DE)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Universitätsklinikum Würzburg (DE)
  • Privatpraxis für Muskel- und Knochenkrankheiten, 12163 Berlin Germany
Corresponding author
Jakob, Franz
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2020-03-10
Volume
10
Issue
3
Pages
432
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom10030432
PMC
PMC7175139
OpenAlex
W3010713274
Cited by
197
References
217
Citations by year
2026: 23 · 2025: 41 · 2024: 43 · 2023: 32 · 2022: 33 · 2021: 17 · 2020: 6 · 2019: 1
FWCI
2.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
  • OPUS Repository (Kooperativer Bibliotheksverbund Berlin-Brandenburg) (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (TRR 225, JU426/5-1, 326998133, 01EC1402C, D-361)
  • Bundesministerium für Bildung und Forschung (326998133-TRR 225, 01EC1402C, 326998133)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Physiology › Spaceflight effects on biology
Keywords
muscle-bone interaction, mechanotransduction, osteokines, myokines, exosomes, extracellular matrix, muscle hypertrophy, bone formation, physical activity, microgravity, disuse, sarcopenia, osteoporosis, bone marrow adiposity, tissue stiffness
MeSH terms
Bone and Bones, Extracellular Matrix, Humans, Osteoporosis, Exercise, Muscle, Skeletal, Mechanotransduction, Cellular, Sarcopenia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review