Dynamics of muscle-bone crosstalk throughout lifespan

Abstract

Operating as a physically and physiologically integrated unit, skeletal muscle and bone are fundamental to human mobility and metabolism. Their reciprocal crosstalk endures throughout life. In early embryonic development, with a primary focus on morphogenesis, skeletal muscle and bone actively drive the functional maturation of both tissues during development. When the interplay reaches relative homeostasis during adulthood, they reciprocally sustain the functional integrity and physiological homeostasis of one another. With aging, however, this intimate connection exacerbates reciprocal decline, initiating a pathological feed-forward loop that precipitates osteosarcopenia. As this crosstalk is orchestrated by a shifting matrix of mediators, from biomechanical loads to neuronal, immunological, and secretory signals, understanding their age-associated alterations may help provide a point of intervention for treatment. This review outlines dynamic changes in muscle-bone crosstalk throughout the lifespan, discusses longitudinal changes in aging, and provides stage-specific perspectives for intervention.

Keywords

Muscle-bone crosstalk / lifespan / biomechanical load / myokines / osteokines / extracellular vesicles / neural and immune regulation / lifelong intervention

1 Acknowledgements

The authors declare that Gemini 3.1 PRO was used solely for language polishing during the manuscript preparation process. The authors take full responsibility for the integrity, originality, and accuracy of the work.

2 Authors contribution

Tang C, Yin X: Investigation, data curation, formal analysis, writing-original draft, writing review & editing.

Zhang H: Writing review & editing.

3 Conflicts of interest

Hongbo Zhang is an Editorial Board Member of Ageing and Cancer Research & Treatment. The other authors declare no conflicts of interest.

4 Ethical approval

Not applicable.

5 Consent to participate

Not applicable.

6 Consent for publication

Not applicable.

7 Availability of data and materials

Not applicable.

Funding

This work was supported by the Ministry of Science and Technology of China (Grant Nos. 2022YFA1104900 and 2024ZD0530500), the National Natural Science Foundation of China (Grant Nos. W2511023 and 31871370), the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China (Grant No. KF-202503), the Guangzhou Science and Technology Planning Project (Grant No. 2024A04J4614) and the Fundamental Research Funds for the Central Universities (Grant No. 24ykzy002).

References

[1] Kirk B, Lombardi G, Duque G. Bone and muscle crosstalk in ageing and disease. Nat Rev Endocrinol. 2025; 21(6):375-390.

[2] Frontera WR, Ochala J. Skeletal muscle: A brief review of structure and function. Calcif Tissue Int. 2015; 96(3):183-195.

[3] Su N, Yang J, Xie Y, Du X, Chen H, Hong Z, et al. Bone function, dysfunction and its role in diseases including critical illness. Int J Biol Sci. 2019; 15(4):776-787.

[4] Pedersen BK, Febbraio MA. Muscle as an endocrine organ: Focus on muscle-derived interleukin-6. Physiol Rev. 2008; 88(4):1379-1406.

[5] Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007; 130(3):456-469.

[6] Aoi W, Tanimura Y. Roles of skeletal muscle-derived exosomes in organ metabolic and immunological communication. Front Endocrinol. 2021; 12:697204.

[7] Han Y, You X, Xing W, Zhang Z, Zou W. Paracrine and endocrine actions of bone—the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res. 2018; 6:16.

[8] Brotto M, Bonewald L. Bone and muscle: Interactions beyond mechanical. Bone. 2015; 80:109-114.

[9] Zhi X, Chen Q, Song S, Gu Z, Wei W, Chen H, et al. Myostatin promotes osteoclastogenesis by regulating Ccdc50 gene expression and RANKL-induced NF-κB and MAPK pathways. Front Pharmacol. 2020; 11:565163.

[10] Zhong C, Zeng X, Yi X, Yang Y, Hu J, Yin R, et al. The function of myostatin in ameliorating bone metabolism abnormalities in individuals with type 2 diabetes mellitus by exercise. Curr Issues Mol Biol. 2025; 47(3):158.

[11] Aryana IGPS, Rini SS, Soejono CH. Importance of sclerostin as bone-muscle mediator crosstalk. Ann Geriatr Med Res. 2022; 26(2):72-82.

[12] Dong Y, Yuan H, Ma G, Cao H. Bone-muscle crosstalk under physiological and pathological conditions. Cell Mol Life Sci. 2024; 81(1):310.

[13] Pai AC. Developmental genetics of a lethal mutation, muscular dysgenesis (mdg), in the mouse. Dev Biol. 1965; 11:93-109.

[14] Blitz E, Viukov S, Sharir A, Shwartz Y, Galloway JL, Pryce BA, et al. Bone ridge patterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon-skeleton junction. Dev Cell. 2009; 17(6):861-873.

[15] Drey M, Sieber CC, Bertsch T, Bauer JM, Schmidmaier R. Osteosarcopenia is more than sarcopenia and osteopenia alone. Aging Clin Exp Res. 2016; 28(5):895-899.

[16] Pang BWJ, Wee SL, Chen KK, Lau LK, Jabbar KA, Seah WT, et al. Coexistence of osteoporosis, sarcopenia and obesity in community-dwelling adults-The Yishun Study. Osteoporos Sarcopenia. 2021; 7(1):17-23.

[17] Xue M, You XH, Wang XY, Xu YJ. Pectoral muscle cross-sectional area correlates with bone mineral density in postmenopausal women. Front Med. 2026; 13:1781151.

[18] Zhang B, Chen Y, Chen Q, Zhang H. Exosomal miRNAs in muscle-bone crosstalk: Mechanistic links, exercise modulation and implications for sarcopenia, osteoporosis and osteosarcopenia. Metabolism. 2025; 170:156333.

[19] Long KK, O’Shea KM, Khairallah RJ, Howell K, Paushkin S, Chen KS, et al. Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy. Hum Mol Genet. 2019; 28(7):1076-1089.

[20] Maurel DB, Jähn K, Lara-Castillo N. Muscle-bone crosstalk: Emerging opportunities for novel therapeutic approaches to treat musculoskeletal pathologies. Biomedicines. 2017; 5(4):62.

[21] Farsani MA, Banitalebi E, Faramarzi M, Bakhtiari N, Rahimi M, Duque G. Bone-muscle crosstalk following exercise plus Ursolic acid by myomiR-133a/Cx43-Runx2 axis in aged type 2 diabetes rat models. Chem Biol Interact. 2023; 370:110315.

[22] Felsenthal N, Zelzer E. Mechanical regulation of musculoskeletal system development. Development. 2017; 144(23):4271-4283.

[23] Leser JM, Harriot A, Buck HV, Ward CW, Stains JP. Aging, osteo-sarcopenia, and musculoskeletal mechano-transduction. Front Rehabil Sci. 2021; 2:782848.

[24] Nowlan NC, Murphy P, Prendergast PJ. Mechanobiology of embryonic limb development. Ann N Y Acad Sci. 2007; 1101(1):389-411.

[25] Sui H, Dou J, Shi B, Cheng X. The reciprocity of skeletal muscle and bone: An evolving view from mechanical coupling, secretory crosstalk to stem cell exchange. Front Physiol. 2024; 15:1349253.

[26] Zhao Z, Yan K, Guan Q, Guo Q, Zhao C. Mechanism and physical activities in bone-skeletal muscle crosstalk. Front Endocrinol. 2024; 14:1287972.

[27] Gomarasca M, Banfi G, Lombardi G. Myokines: The endocrine coupling of skeletal muscle and bone. Adv Clin Chem. 2020; 94:155-218.

[28] Gao S, Li N, Qi L, Li X, Zhang J, Zhang Z, et al. Myokines and osteokines in aging-related degenerative diseases: Regulatory networks in the muscle-bone-brain axis. Cytokine Growth Factor Rev. 2025; 86:17-28.

[29] Oranger A, Storlino G, Dicarlo M, Zerlotin R, Pignataro P, Sanesi L, et al. Impact of 10-day bed rest on serum levels of irisin and markers of musculoskeletal metabolism. FASEB J. 2023; 37(1):e22668.

[30] Kang JS, Kim JH, Kim MJ, Min B, Lee SM, Go GY, et al.Exercise-induced CLCF1 attenuates age-related muscle and bone decline in mice. Nat Commun. 2025; 16(1):4743.

[31] Wang B, Han J, Elisseeff JH, Demaria M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol. 2024; 25(12):958-978.

[32] Brent AE, Braun T, Tabin CJ. Genetic analysis of interactions between the somitic muscle, cartilage and tendon cell lineages during mouse development. Development. 2005; 132(3):515-528.

[33] Zhao Y, Xu K, Wu K, Guo Z, Li H, Lin N, et al. The roles of the nerve-immune axis in modulating bone regeneration. Bone Res. 2026; 14(1):2.

[34] Zhou A, Wu B, Yu H, Tang Y, Liu J, Jia Y, et al. Current understanding of osteoimmunology in certain osteoimmune diseases. Front Cell Dev Biol. 2021; 9:698068.

[35] Hall BK, Herring SW. Paralysis and growth of the musculoskeletal system in the embryonic chick. J Morphol. 1990; 206(1):45-56.

[36] Liu S, Liu S, Li S, Liang B, Han X, Liang Y, et al. Nerves within bone and their application in tissue engineering of bone regeneration. Front Neurol. 2023; 13:1085560.

[37] Malvandi AM, Gerosa L, Banfi G, Lombardi G. The bone-muscle unit: From mechanical coupling to soluble factors-mediated signaling. Mol Aspects Med. 2025; 103:101367.

[38] Jacome-Galarza CE, Percin GI, Muller JT, Mass E, Lazarov T, Eitler J, et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature. 2019; 568(7753):541-545.

[39] Yahara Y, Nguyen T, Ishikawa K, Kamei K, Alman BA. The origins and roles of osteoclasts in bone development, homeostasis and repair. Development. 2022; 149(8):dev199908.

[40] Hall JG. In utero movement and use of limbs are necessary for normal growth: A study of individuals with arthrogryposis. Prog Clin Biol Res. 1985; 200:155-162.

[41] Pollard AS, Charlton BG, Hutchinson JR, Gustafsson T, McGonnell IM, Timmons JA, et al. Limb proportions show developmental plasticity in response to embryo movement. Sci Rep. 2017; 7:41926.

[42] Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003; 423(6937):332-336.

[43] Trompet D, Kurenkova AD, Zhou B, Li L, Dregval O, Usanova AP, et al. Stimulation of skeletal stem cells in the growth plate promotes linear bone growth. JCI Insight. 2024; 9(6):e165226.

[44] Stoop J, Yokoyama Y, Adachi T. Timing of resting zone parathyroid hormone-related protein expression affects maintenance of the growth plate during secondary ossification: A computational study. Biomech Model Mechanobiol. 2025; 24(1):125-137.

[45] Deng Y, Wu A, Li P, Li G, Qin L, Song H, et al. Yap1 regulates multiple steps of chondrocyte differentiation during skeletal development and bone repair. Cell Rep. 2016; 14(9):2224-2237.

[46] Esteves de Lima J, Bonnin MA, Birchmeier C, Duprez D. Muscle contraction is required to maintain the pool of muscle progenitors via YAP and NOTCH during fetal myogenesis. eLife. 2016; 5:e15593.

[47] Zhou T, Gao B, Fan Y, Liu Y, Feng S, Cong Q, et al. Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-ß-catenin. eLife. 2020; 9:e52779.

[48] Hendrickx G, Fischer V, Liedert A, von Kroge S, Haffner-Luntzer M, Brylka L, et al. Piezo1 inactivation in chondrocytes impairs trabecular bone formation. J Bone Miner Res. 2021; 36(2):369-384.

[49] Rodríguez JI, Palacios J, Ruiz A, Sanchez M, Alvarez I, Demiguel E. Morphological changes in long bone development in fetal akinesia deformation sequence: An experimental study in curarized rat fetuses. Teratology. 1992; 45(2):213-221.

[50] Gomez C, David V, Peet NM, Vico L, Chenu C, Malaval L, et al. Absence of mechanical loading in utero influences bone mass and architecture but not innervation in Myod-Myf5-deficient mice. J Anat. 2007; 210(3):259-271.

[51] Sharir A, Stern T, Rot C, Shahar R, Zelzer E. Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis. Development. 2011; 138(15):3247-3259.

[52] Murchison ND, Price BA, Conner DA, Keene DR, Olson EN, Tabin CJ, et al. Regulation of tendon differentiation by scleraxis distinguishes force-transmitting tendons from muscle-anchoring tendons. Development. 2007; 134(14):2697-2708.

[53] Kardon G. Muscle and tendon morphogenesis in the avian hind limb. Development. 1998; 125(20):4019-4032.

[54] Yu X, Kawakami R, Yambe S, Yoshimoto Y, Sasaki T, Higuchi S, et al. Dynamic interactions between cartilaginous and tendinous/ligamentous primordia during musculoskeletal integration. Development. 2025; 152(6):dev204512.

[55] Kahn J, Shwartz Y, Blitz E, Krief S, Sharir A, Breitel DA, et al. Muscle contraction is necessary to maintain joint progenitor cell fate. Dev Cell. 2009; 16(5):734-743.

[56] Brent AE, Schweitzer R, Tabin CJ. A somitic compartment of tendon progenitors. Cell. 2003; 113(2):235-248.

[57] Huang R, Stolte D, Kurz H, Ehehalt F, Cann GM, Stockdale FE, et al. Ventral axial organs regulate expression of myotomal Fgf-8 that influences rib development. Dev Biol. 2003; 255(1):30-47.

[58] Nowlan NC, Sharpe J, Roddy KA, Prendergast PJ, Murphy P. Mechanobiology of embryonic skeletal development: Insights from animal models. Birth Defects Res C Embryo Today. 2010; 90(3):203-213.

[59] Panebianco CJ, Huang Y, Khatib N, Gottlieb DC, Essaidi M, Ahmed S, et al. Maternal exercise rescues fetal akinesia-impaired joint and bone development. FASEB J. 2025; 39(24):e71341.

[60] Kartsogiannis V, Zhou H, Horwood NJ, Thomas RJ, Hards DK, Quinn JMW, et al. Localization of RANKL (receptor activator of NFκB ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone. 1999; 25(5):525-534.

[61] Boulanger Piette A, Hamoudi D, Marcadet L, Morin F, Argaw A, Ward L, et al. Targeting the muscle-bone unit: Filling two needs with one deed in the treatment of Duchenne muscular dystrophy. Curr Osteoporos Rep. 2018; 16(5):541-553.

[62] Bonnet N, Bourgoin L, Biver E, Douni E, Ferrari S. RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass. J Clin Invest. 2023; 133(4):e169317.

[63] Lin X, Parker L, McLennan E, Hayes A, McConell G, Brennan-Speranza TC, et al. Undercarboxylated osteocalcin improves insulin-stimulated glucose uptake in muscles of corticosterone-treated mice. J Bone Miner Res. 2019; 34(8):1517-1530.

[64] Lin X, Parker L, McLennan E, Zhang X, Hayes A, McConell G, et al. Recombinant uncarboxylated osteocalcin per Se enhances mouse skeletal muscle glucose uptake in both extensor digitorum longus and soleus muscles. Front Endocrinol. 2017; 8:330.

[65] Liu S, Gao F, Wen L, Ouyang M, Wang Y, Wang Q, et al. Osteocalcin induces proliferation via positive activation of the PI3K/Akt, P38 MAPK pathways and promotes differentiation through activation of the GPRC6A-ERK1/2 pathway in C2C 12 myoblast cells. Cell Physiol Biochem. 2017; 43(3):1100-1112.

[66] Oury F, Khrimian L, Denny CA, Gardin A, Chamouni A, Goeden N, et al. Maternal and offspring pools of osteocalcin influence brain development and functions. Cell. 2013; 155(1):228-241.

[67] Santoso JW, Do SK, Verma R, Do AV, Hendricks E, Ichida JK, et al. Human iPSC-derived motor neuron innervation enhances the differentiation of muscle bundles engineered with benchtop fabrication techniques. ACS Biomater Sci Eng. 2025; 11(3):1731-1740.

[68] Saini J, Faroni A, Reid AJ, Mouly V, Butler-Browne G, Lightfoot AP, et al. Cross-talk between motor neurons and myotubes via endogenously secreted neural and muscular growth factors. Physiol Rep. 2021; 9(8):e14791.

[69] Routledge D, Scholpp S. Mechanisms of intercellular Wnt transport. Development. 2019; 146(10):dev176073.

[70] McGough IJ, Vincent JP. Exosomes in developmental signalling. Development. 2016; 143(14):2482-2493.

[71] Xing Z, Guo L, Li S, Huang W, Su J, Chen X, et al. Skeletal muscle-derived exosomes prevent osteoporosis by promoting osteogenesis. Life Sci. 2024; 357:123079.

[72] Yan Y, Zheng M, Wang X, Fu T, Qi J, Wei X, et al. miR-126-5p derived from bone marrow mesenchymal stem cell exosomes promotes skeletal muscle regeneration by regulating FBXO32/MyoD signaling. Acta Physiol. 2025; 241(11):e70114.

[73] Tomlinson RE, Li Z, Zhang Q, Goh BC, Li Z, Thorek DLJ, et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep. 2016; 16(10):2723-2735.

[74] Tao R, Mi B, Hu Y, Lin S, Xiong Y, Lu X, et al. Hallmarks of peripheral nerve function in bone regeneration. Bone Res. 2023; 11:6.

[75] Crow MT, Stockdale FE. Myosin expression and specialization among the earliest muscle fibers of the developing avian limb. Dev Biol. 1986; 113(1):238-254.

[76] Wu H, Xiong WC, Mei L. To build a synapse: Signaling pathways in neuromuscular junction assembly. Development. 2010; 137(7):1017-1033.

[77] Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev. 2011; 91(4):1447-1531.

[78] Harris AJ, Harris A. Embryonic growth and innervation of rat skeletal muscles I. Neural regulation of muscle fibre numbers. Philos Trans R Soc Lond B Biol Sci. 1981; 293(1065):257-277.

[79] Brandon EP, Lin W, D’Amour KA, Pizzo DP, Dominguez B, Sugiura Y, et al. Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. J Neurosci. 2003; 23(2):539-549.

[80] Sohal GS, Holt RK. Role of innervation on the embryonic development of skeletal muscle. Cell Tissue Res. 1980; 210(3):383-393.

[81] Madaro L, Passafaro M, Sala D, Etxaniz U, Lugarini F, Proietti D, et al. Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nat Cell Biol. 2018; 20(8):917-927.

[82] Hopkinson-Woolley J, Hughes D, Gordon S, Martin P. Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. J Cell Sci. 1994; 107(5):1159-1167.

[83] Wood W, Martin P. Macrophage functions in tissue patterning and disease: New insights from the fly. Dev Cell. 2017; 40(3):221-233.

[84] Fan A, Zhang J, Ye Q. Osteosarcopenia in metabolic dysfunction-associated steatotic liver disease: From mechanisms to management. Front Endocrinol. 2025; 16:1706068.

[85] Lee PHU, Chung M, Ren Z, Mair DB, Kim DH. Factors mediating spaceflight-induced skeletal muscle atrophy. Am J Physiol Cell Physiol. 2022; 322(3):C567-C580.

[86] Lei L, Wen Z, Cao M, Zhang H, Ling SK, Fu BS, et al. The emerging role of Piezo1 in the musculoskeletal system and disease. Theranostics. 2024; 14(10):3963-3983.

[87] Wang L, You X, Zhang L, Zhang C, Zou W. Mechanical regulation of bone remodeling. Bone Res. 2022; 10:16.

[88] Kirk B, Feehan J, Lombardi G, Duque G. Muscle, bone, and fat crosstalk: The biological role of myokines, osteokines, and adipokines. Curr Osteoporos Rep. 2020; 18(4):388-400.

[89] Ning K, Wang Z, Zhang XA. Exercise-induced modulation of myokine irisin in bone and cartilage tissue: Positive effects on osteoarthritis: A narrative review. Front Aging Neurosci. 2022; 14:934406.

[90] Kitase Y, Vallejo JA, Gutheil W, Vemula H, Jähn K, Yi J, et al. β-aminoisobutyric acid, l-BAIBA, is a muscle-derived osteocyte survival factor. Cell Rep. 2018; 22(6):1531-1544.

[91] Vinel C, Lukjanenko L, Batut A, Deleruyelle S, Pradère JP, Le Gonidec S, et al. The exerkine apelin reverses age-associated sarcopenia. Nat Med. 2018; 24(9):1360-1371.

[92] Mera P, Laue K, Wei J, Berger JM, Karsenty G. Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab. 2016; 5(10):1042-1047.

[93] Mera P, Laue K, Ferron M, Confavreux C, Wei J, Galán-Díez M, et al. Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab. 2016; 23(6):1078-1092.

[94] Frühbeis C, Helmig S, Tug S, Simon P, Krämer-Albers EM. Physical exercise induces rapid release of small extracellular vesicles into the circulation. J Extracell Vesicle. 2015; 4:28239.

[95] Guescini M, Canonico B, Lucertini F, Maggio S, Annibalini G, Barbieri E, et al. Muscle releases alpha-sarcoglycan positive extracellular vesicles carrying miRNAs in the bloodstream. PLoS One. 2015; 10(5):e0125094.

[96] Ma S, Xing X, Huang H, Gao X, Xu X, Yang J, et al. Skeletal muscle-derived extracellular vesicles transport glycolytic enzymes to mediate muscle-to-bone crosstalk. Cell Metab. 2023; 35(11):2028-2043.

[97] Whitham M, Parker BL, Friedrichsen M, Hingst JR, Hjorth M, Hughes WE, et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 2018; 27(1):237-251.

[98] Yi M, Wu Y, Long J, Liu F, Liu Z, Zhang YH, et al. Exosomes secreted from osteocalcin-overexpressing endothelial progenitor cells promote endothelial cell angiogenesis. Am J Physiol Cell Physiol. 2019; 317(5):C932-C941.

[99] Tintignac LA, Brenner HR, Rüegg MA. Mechanisms regulating neuromuscular junction development and function and causes of muscle wasting. Physiol Rev. 2015; 95(3):809-852.

[100] Iyer SR, Shah SB, Lovering RM. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021; 22(15):8058.

[101] Watt KI, Turner BJ, Hagg A, Zhang X, Davey JR, Qian H, et al. The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size. Nat Commun. 2015; 6:6048.

[102] Goodman CA, Dietz JM, Jacobs BL, McNally RM, You JS, Hornberger TA. Yes-Associated Protein is up-regulated by mechanical overload and is sufficient to induce skeletal muscle hypertrophy. FEBS Lett. 2015; 589(13):1491-1497.

[103] Yang Z, Nakagawa K, Sarkar A, Maruyama J, Iwasa H, Bao Y, et al. Screening with a novel cell-based assay for TAZ activators identifies a compound that enhances myogenesis in C2C12 cells and facilitates muscle repair in a muscle injury model. Mol Cell Biol. 2014; 34(9):1607-1621.

[104] Watt KI, Henstridge DC, Ziemann M, Sim CB, Montgomery MK, Samocha-Bonet D, et al. Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease. Nat Commun. 2021; 12(1):2887.

[105] Bernard C, Zavoriti A, Pucelle Q, Chazaud B, Gondin J. Role of macrophages during skeletal muscle regeneration and hypertrophy-Implications for immunomodulatory strategies. Physiol Rep. 2022; 10(19):e15480.

[106] Tidball JG. Regulation of muscle growth and regeneration by the immune system. Nat Rev Immunol. 2017; 17(3):165-178.

[107] Chang MK, Raggatt LJ, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K, et al. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol. 2008; 181(2):1232-1244.

[108] Batoon L, Millard SM, Raggatt LJ, Pettit AR. Osteomacs and bone regeneration. Curr Osteoporos Rep. 2017; 15(4):385-395.

[109] Hirschfeld HP, Kinsella R, Duque G. Osteosarcopenia: Where bone, muscle, and fat collide. Osteoporos Int. 2017; 28(10):2781-2790.

[110] Colaianni G, Errede M, Sanesi L, Notarnicola A, Celi M, Zerlotin R, et al. Irisin correlates positively with BMD in a cohort of older adult patients and downregulates the senescent marker p 21 in osteoblasts. J Bone Miner Res. 2021; 36(2):305-314.

[111] Perrini S, Laviola L, Carreira MC, Cignarelli A, Natalicchio A, Giorgino F. The GH/IGF1 axis and signaling pathways in the muscle and bone: Mechanisms underlying age-related skeletal muscle wasting and osteoporosis. J Endocrinol. 2010; 205(3):201-210.

[112] Gellhaus B, Böker KO, Schilling AF, Saul D. Therapeutic consequences of targeting the IGF-1/PI3K/AKT/FOXO3 axis in sarcopenia: A narrative review. Cells. 2023; 12(24):2787.

[113] Scicchitano BM, Rizzuto E, Musarò A. Counteracting muscle wasting in aging and neuromuscular diseases: The critical role of IGF-1. Aging. 2009; 1(5):451-457.

[114] Kim KW, Cho HJ, Khaliq SA, Son KH, Yoon MS. Comparative analyses of mTOR/Akt and muscle atrophy-related signaling in aged respiratory and gastrocnemius muscles. Int J Mol Sci. 2020; 21(8):2862.

[115] Xian L, Wu X, Pang L, Lou M, Rosen CJ, Qiu T, et al. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med. 2012; 18(7):1095-1101.

[116] Sasako T, Umehara T, Soeda K, Kaneko K, Suzuki M, Kobayashi N, et al. Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice. Nat Commun. 2022; 13:5655.

[117] Cano-Martínez A, Méndez-Castro JA, García-Vázquez VE, Carreón-Torres E, Díaz-Díaz E, Sánchez-Aguilar M, et al. A combination of resveratrol and quercetin prevents sarcopenic obesity: Its role as a signaling inhibitor of Myostatin/ActRIIA and ActRIIB/Smad and as an enhancer of insulin actions. Int J Mol Sci. 2025; 26(10):4952.

[118] Egerman MA, Zhang Y, Donne R, Xu J, Gadi A, McEwen C, et al. ActRII or BMPR ligands inhibit skeletal myoblast differentiation, and BMPs promote heterotopic ossification in skeletal muscles in mice. Skelet Muscle. 2025; 15(1):4.

[119] Wijaya YT, Setiawan T, Sari IN, Park K, Lee CH, Cho KW, et al. Ginsenoside Rd ameliorates muscle wasting by suppressing the signal transducer and activator of transcription 3 pathway. J Cachexia Sarcopenia Muscle. 2022; 13(6):3149-3162.

[120] Koide M, Kobayashi Y. Regulatory mechanisms of sclerostin expression during bone remodeling. J Bone Miner Metab. 2019; 37(1):9-17.

[121] Iwamoto R, Koide M, Udagawa N, Kobayashi Y. Positive and negative regulators of sclerostin expression. Int J Mol Sci. 2022; 23(9):4895.

[122] Oh WT, Yang YS, Xie J, Ma H, Kim JM, Park KH, et al. WNT-modulating gene silencers as a gene therapy for osteoporosis, bone fracture, and critical-sized bone defects. Mol Ther. 2023; 31(2):435-453.

[123] Kobayashi T, Yokoyama S, Asakura A, Goto K. A possible physiological role of sclerostin in aging-associated skeletal muscle atrophy. Physiology. 2024; 39(S1):2294.

[124] Magarò MS, Bertacchini J, Florio F, Zavatti M, Potì F, Cavani F, et al. Identification of sclerostin as a putative new myokine involved in the muscle-to-bone crosstalk. Biomedicines. 2021; 9(1):71.

[125] Yin P, Chen M, Rao M, Lin Y, Zhang M, Xu R, et al. Deciphering immune landscape remodeling unravels the underlying mechanism for synchronized muscle and bone aging. Adv Sci. 2024; 11(5):e2304084.

[126] Chung PL, Zhou S, Eslami B, Shen L, LeBoff MS, Glowacki J. Effect of age on regulation of human osteoclast differentiation. J Cell Biochem. 2014; 115(8):1412-1419.

[127] Marcadet L, Bouredji Z, Argaw A, Frenette J. The roles of RANK/RANKL/OPG in cardiac, skeletal, and smooth muscles in health and disease. Front Cell Dev Biol. 2022; 10:903657.

[128] Jayash SN, Hamoudi D, Stephen LA, Argaw A, Huesa C, Joseph S, et al. Anti-RANKL therapy prevents glucocorticoid-induced bone loss and promotes muscle function in a mouse model of duchenne muscular dystrophy. Calcif Tissue Int. 2023; 113(4):449-468.

[129] Cavalcanti de Araújo PH, Cezine MER, Vulczak A, Vieira LC, Matsuo FS, Remoto JM, et al. RANKL signaling drives skeletal muscle into the oxidative profile. J Bone Miner Res. 2024; 39(6):753-764.

[130] Chowdhury S, Schulz L, Palmisano B, Singh P, Berger JM, Yadav VK, et al. Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts. J Clin Invest. 2020; 130(6):2888-2902.

[131] Wang J, Leung KS, Chow SK, Cheung WH. Inflammation and age-associated skeletal muscle deterioration (sarcopaenia). J Orthop Transl. 2017; 10:94-101.

[132] Li Y, Lu L, Xie Y, Chen X, Tian L, Liang Y, et al. Interleukin-6 knockout inhibits senescence of bone mesenchymal stem cells in high-fat diet-induced bone loss. Front Endocrinol. 2021; 11:622950.

[133] Liu M, Han Y, Wang J, Zhu Y, Zhang Y, Chu Q, et al. Skeletal muscle-derived IL-33 mediates muscle-to-bone crosstalk and regulates bone metabolism via CD8⁺ T cell-secreted CCL5. eBioMedicine. 2025; 122:106024.

[134] Kang H, Yang K, Xiao L, Guo L, Guo C, Yan Y, et al. Osteoblast hypoxia-inducible factor-1α pathway activation restrains osteoclastogenesis via the interleukin-33-MicroRNA-34a-Notch 1 pathway. Front Immunol. 2017; 8:1312.

[135] Ohori F, Kitaura H, Ogawa S, Shen WR, Qi J, Noguchi T, et al. IL-33 inhibits TNF-α-induced osteoclastogenesis and bone resorption. Int J Mol Sci. 2020; 21(3):1130.

[136] Cordero da Luz FA, Lima Oliveira AP, Borges D, Cristina Brígido P, Barbosa Silva MJ. The physiopathological role of IL-33: New highlights in bone biology and a proposed role in periodontal disease. Mediat Inflamm. 2014; 2014:342410.

[137] Arnold WD, Clark BC. Neuromuscular junction transmission failure in aging and sarcopenia: The nexus of the neurological and muscular systems. Ageing Res Rev. 2023; 89:101966.

[138] Xu H, Ranjit R, Richardson A, Van Remmen H. Muscle mitochondrial catalase expression prevents neuromuscular junction disruption, atrophy, and weakness in a mouse model of accelerated sarcopenia. J Cachexia Sarcopenia Muscle. 2021; 12(6):1582-1596.

[139] Cisterna BA, Vargas AA, Puebla C, Fernández P, Escamilla R, Lagos CF, et al. Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation. Nat Commun. 2020; 11(1):1073.

[140] Hassan MG, Horenberg AL, Coler-Reilly A, Grayson WL, Scheller EL. Role of the peripheral nervous system in skeletal development and regeneration: Controversies and clinical implications. Curr Osteoporos Rep. 2023; 21(5):503-518.

[141] Wu Z, Li N, Luo Z, Chen Z, He X, Shi F, et al. The p75 neurotrophin receptor controls the skeletal stem cell niche through sensory innervation. Dev Cell. 2026; 61(2):259-275.

[142] Alfonzo MC, Al Saedi A, Fulzele S, Hamrick MW. Extracellular vesicles as communicators of senescence in musculoskeletal aging. JBMR Plus. 2022; 6(11):e10686.

[143] Fulzele S, Mendhe B, Khayrullin A, Johnson M, Kaiser H, Liu Y, et al. Muscle-derived miR-34a increases with age in circulating extracellular vesicles and induces senescence of bone marrow stem cells. Aging. 2019; 11(6):1791-1803.

[144] Borja-Gonzalez M, Casas-Martinez JC, McDonagh B, Goljanek-Whysall K.Aging Science Talks:The role of miR-181a in age-related loss of muscle mass and function. Transl Med Aging. 2020; 4:81-85.

[145] Jing D, Hao J, Shen Y, Tang G, Li ML, Huang SH, et al. The role of microRNAs in bone remodeling. Int J Oral Sci. 2015; 7(3):131-143.

[146] Goljanek-Whysall K, Soriano-Arroquia A, McCormick R, Chinda C, McDonagh B. miR-181a regulates p62/SQSTM1, parkin, and protein DJ-1 promoting mitochondrial dynamics in skeletal muscle aging. Aging Cell. 2020; 19(4):e13140.

[147] Faraldi M, Sansoni V, Vitale J, Perego S, Gomarasca M, Verdelli C, et al. Plasma microRNA signature associated with skeletal muscle wasting in post-menopausal osteoporotic women. J Cachexia Sarcopenia Muscle. 2024; 15(2):690-701.

[148] Mytidou C, Koutsoulidou A, Zachariou M, Prokopi M, Kapnisis K, Spyrou GM, et al. Age-Related Exosomal and Endogenous Expression Patterns of miR-1, miR-133a, miR-133b, and miR-206 in skeletal muscles. Front Physiol. 2021; 12:708278.

[149] Shao X, Zhang P, Fan Z, Lin J, Chen X, Liu N, et al. Atrophic skeletal muscle-derived extracellular vesicles transfer miR-125a-5p to inhibit bone formation in osteoporosis during aging. Adv Sci. 2026; 13(25):e15362.

[150] Li D, Liu J, Guo B, Liang C, Dang L, Lu C, et al. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat Commun. 2016; 7:10872.

[151] Liu J, Xia F, Huang T, Sheng Y, Ding G, Duan Y, et al. Aged small intestine derived small extracellular vesicles miR-214-3p leads to intermuscular fatty infiltration through Wnt/β-catenin mediated fibro-adipogenic progenitors adipogenesis. FASEB J. 2026; 40(3):e71527.

[152] György B, Szatmári R, Ditrói T, Torma F, Pálóczi K, Balbisi M, et al. The protein cargo of extracellular vesicles correlates with the epigenetic aging clock of exercise sensitive DNAmFitAge. Biogerontology. 2025; 26(1):35.

[153] Gatti M, Beretti F, Malenchini M, Bertucci E, Ceneri E, Follo MY, et al. Mesenchymal stromal cell-derived extracellular vesicles as a therapeutic treatment for osteosarcopenia: Crosstalk among neurons, muscle, and bone. Int J Mol Sci. 2025; 26(16):7875.

[154] Pauk M, Saito H, Hesse E, Taipaleenmäki H. Muscle and bone defects in metastatic disease. Curr Osteoporos Rep. 2022; 20(5):273-289.

[155] Regan JN, Trivedi T, Guise TA, Waning DL. The role of TGFβ in bone-muscle crosstalk. Curr Osteoporos Rep. 2017; 15(1):18-23.

[156] Hain BA, Waning DL. Bone-muscle crosstalk: Musculoskeletal complications of chemotherapy. Curr Osteoporos Rep. 2022; 20(6):433-441.

[157] Ballinger TJ, Thompson WR, Guise TA. The bone-muscle connection in breast cancer: Implications and therapeutic strategies to preserve musculoskeletal health. Breast Cancer Res. 2022; 24(1):84.

[158] Azzolino D, Spolidoro GCI, Saporiti E, Luchetti C, Agostoni C, Cesari M. Musculoskeletal changes across the lifespan: Nutrition and the life-course approach to prevention. Front Med. 2021; 8:697954.

[159] Kirk B, Zanker J, Duque G. Osteosarcopenia: Epidemiology, diagnosis, and treatment-facts and numbers. J Cachexia Sarcopenia Muscle. 2020; 11(3):609-618.

[160] Bunn RC, Adatorwovor R, Smith RR, Ray PD, Fields SE, Keeble AR, et al. Pharmacologic inhibition of myostatin with a myostatin antibody improves the skeletal muscle and bone phenotype of male insulin-deficient diabetic mice. JBMR Plus. 2023; 7(11):e10833.

[161] Wetzlich B, Nyakundi BB, Yang J. Therapeutic applications and challenges in myostatin inhibition for enhanced skeletal muscle mass and functions. Mol Cell Biochem. 2025; 480(3):1535-1553.

[162] Zhou B, Hu J, Yu Y, Sun L, Wang Y, Zhang Q, et al. Novel aptamers targeting sclerostin Loop3 improve skeletal and muscle properties without adverse cardiovascular effects in orchiectomized mice. J Cachexia Sarcopenia Muscle. 2025; 16(3):e13831.

[163] Yi YT, Zhao HF, Wang WZ, Li X. Osteosarcopenia: Epidemiology, molecular mechanisms, and management. Front Endocrinol. 2025; 16:1577758.

[164] Bernareggi A, Bosutti A, Massaria G, Giniatullin R, Malm T, Sciancalepore M, et al. The state of the art of Piezo1 channels in skeletal muscle regeneration. Int J Mol Sci. 2022; 23(12):6616.

[165] Du Y, Xu B, Li Q, Peng C, Yang K. The role of mechanically sensitive ion channel Piezo1 in bone remodeling. Front Bioeng Biotechnol. 2024; 12:1342149.

[166] Mohammad Rahimi GR, Bijeh N, Rashidlamir A. Effects of exercise training on serum preptin, undercarboxylated osteocalcin and high molecular weight adiponectin in adults with metabolic syndrome. Exp Physiol. 2020; 105(3):449-459.

[167] Liu J, Jia S, Yang Y, Piao L, Wang Z, Jin Z, et al. Exercise induced meteorin-like protects chondrocytes against inflammation and pyroptosis in osteoarthritis by inhibiting PI3K/Akt/NF-κB and NLRP3/caspase-1/GSDMD signaling. Biomed Pharmacother. 2023; 158:114118.

[168] Boudenot A, Pallu S, Uzbekov R, Dolleans E, Toumi H, Lespessailles E. Free-fall landing and interval running have different effects on trabecular bone mass and microarchitecture, serum osteocalcin, biomechanical properties, SOST expression and on osteocyte-related characteristics. Appl Physiol Nutr Metab. 2021; 46(12):1525-1534.

[169] Li Y, Wu Q, Wang J, Ding J, He J. Exerkine-loaded exosomes in muscle aging: A nexus of exercise, regeneration, and crosstalk. Front Cell Dev Biol. 2026; 14:1706977.

[170] Jia J, Wang L, Zhou Y, Zhang P, Chen X. Muscle-derived extracellular vesicles mediate crosstalk between skeletal muscle and other organs. Front Physiol. 2025; 15:1501957.

[171] Novelli G, Calcaterra G, Casciani F, Pecorelli S, Mehta JL. ‘Exerkines’: A comprehensive term for the factors produced in response to exercise. Biomedicines. 2024; 12(9):1975.

[172] Burke BI, Ismaeel A, Long DE, Depa LA, Coburn PT, Goh J, et al. Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise. JCI Insight. 2024; 9(21):e182589.

[173] Nie Y, Sato Y, Garner RT, Kargl C, Wang C, Kuang S, et al. Skeletal muscle-derived exosomes regulate endothelial cell functions via reactive oxygen species-activated nuclear factor-κB signalling. Exp Physiol. 2019; 104(8):1262-1273.

[174] Li Z, Liu C, Li S, Li T, Li Y, Wang N, et al. BMSC-derived exosomes inhibit dexamethasone-induced muscle atrophy via the miR-486-5p/FOXO 1 axis. Front Endocrinol. 2021; 12:681267.

[175] Müller L, Di Benedetto S. Immunosenescence and inflammaging: Mechanisms and modulation through diet and lifestyle. Front Immunol. 2025; 16:1708280.

[176] Xiao H, Ren J. Exercise ameliorates immunosenescence: From mechanisms to interventions. Biology. 2026; 15(1):58.

[177] Englund DA, Sakamoto AE, Fritsche CM, Heeren AA, Zhang X, Kotajarvi BR, et al. Exercise reduces circulating biomarkers of cellular senescence in humans. Aging Cell. 2021; 20(7):e13415.

[178] Garza AP, Morton L, Motsch AL, Puta C, Stiebler M, Lading Y, et al. Acute exercise alters immune responses in older adults, with extracellular vesicle changes observed in a high-intensity intervention. Front Immunol. 2025; 16:1661161.

[179] Marędziak M, Śmieszek A, Chrząstek K, Basinska K, Marycz K. Physical activity increases the total number of bone-marrow-derived mesenchymal stem cells, enhances their osteogenic potential, and inhibits their adipogenic properties. Stem Cells Int. 2015; 2015:379093.

[180] Singulani MP, Stringhetta-Garcia CT, Santos LF, Morais SRL, Louzada MJQ, Oliveira SHP, et al. Effects of strength training on osteogenic differentiation and bone strength in aging female Wistar rats. Sci Rep. 2017; 7:42878.

[181] Karacan I, Türker KS. Exploring neuronal mechanisms of osteosarcopenia in older adults. J Physiol. 2026; 604(2):672-688.

[182] Wang Q, Cui C, Zhang N, Lin W, Chai S, Chow SK, et al. Effects of physical exercise on neuromuscular junction degeneration during ageing: A systematic review. J Orthop Transl. 2024; 46:91-102.

[183] Nishimune H, Stanford JA, Mori Y. Role of exercise in maintaining the integrity of the neuromuscular junction. Muscle Nerve. 2014; 49(3):315-324.

[184] Shin DI, Jin YJ, Noh S, Yun HW, Park DY, Min BH. Exosomes secreted during myogenic differentiation of human fetal cartilage-derived progenitor cells promote skeletal muscle regeneration through miR-145-5p. Tissue Eng Regen Med. 2024; 21(3):487-497.