{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:59:19Z","timestamp":1790513959924,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Transforming growth factor-beta (TGF-\u03b2) is part of a family of molecules that is present in many body tissues and performs many different functions. Evidence has been obtained from mice and human cancer patients with bony metastases and non-metastatic disease, as well as pediatric burn patients, that inflammation leads to bone resorption and release of TGF-\u03b2 from the bone matrix with paracrine effects on muscle protein balance, possibly mediated by the generation of reactive oxygen species. Whether immobilization, which confounds the etiology of bone resorption in burn injury, also leads to the release of TGF-\u03b2 from bone contributing to muscle wasting in other conditions is unclear. The use of anti-resorptive therapy in both metastatic cancer patients and pediatric burn patients has been successful in the prevention of muscle wasting, thereby creating an additional therapeutic niche for this class of drugs. The liberation of TGF-\u03b2 may be one way in which bone helps to control muscle mass, but further investigation will be necessary to assess whether the rate of bone resorption is the determining factor for the release of TGF-\u03b2. Moreover, whether different resorptive conditions, such as immobilization and hyperparathyroidism, also involve TGF-\u03b2 release in the pathogenesis of muscle wasting needs to be investigated.<\/jats:p>","DOI":"10.3390\/ijms23031167","type":"journal-article","created":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T08:37:18Z","timestamp":1642754238000},"page":"1167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Transforming Growth Factor-Beta in Skeletal Muscle Wasting"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3011-4186","authenticated-orcid":false,"given":"Gordon L.","family":"Klein","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Texas Medical Branch, Galveston, TX 77555-0165, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1002\/mus.20150","article-title":"Localization and early time course of TGF-beta 1 mRNA expression in dystrophic muscle","volume":"30","author":"Gosselin","year":"2004","journal-title":"Muscle Nerve"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1111\/iep.12142","article-title":"Changes in calsequestrin, TNF-\u03b1, TGF-\u03b2, and MyoD levels during the progression of skeletal muscle dystrophy in mdx mice: A comparative analysis of the quadriceps, diaphragm, and intrinsic laryngeal muscles","volume":"96","author":"Ferretti","year":"2015","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e135703","DOI":"10.1172\/jci.insight.135703","article-title":"TGF-beta-driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse model","volume":"5","author":"Mazala","year":"2020","journal-title":"JCI Insight"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1002\/jcsm.12650","article-title":"TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy","volume":"12","author":"Xu","year":"2021","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"jcs232157","DOI":"10.1242\/jcs.232157","article-title":"Cross-talk between TGF-\u03b2 and PDGFR-\u03b1 signaling pathways regulates the fate of stromal fibro-adipogenic precursors","volume":"132","author":"Contreras","year":"2019","journal-title":"J. Cell Sci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gonzalez, D., Contreras, O., Rebolledo, D.L., Espinoza, J.P., van Zundert, B., and Brandan, E. (2017). ALS skeletal muscle shows enhanced TGF-\u03b2 signaling, fibrosis, and fibroadipogenic progenitor markers. PLoS ONE., 12.","DOI":"10.1371\/journal.pone.0177649"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1515\/hsz-2017-0217","article-title":"TGF-beta requires the activation of canonical and non-canonical signaling pathways to induce skeletal muscle atrophy","volume":"399","author":"Abrigo","year":"2018","journal-title":"Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1159\/000452522","article-title":"Angiotensin-(1-7) prevents skeletal muscle atrophy induced by Transforming Growth Factor-type beta (TGF-beta) via Mas receptor activation","volume":"40","author":"Abrigo","year":"2016","journal-title":"Cell Physiol. Biochem."},{"key":"ref_9","first-page":"43P","article-title":"Changes in renal function associated with the development of resistance of the renal vasculature to the arterial infusion of angiotensin","volume":"215","author":"Klein","year":"1971","journal-title":"J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1038\/nm.3961","article-title":"Excess TGF-\u03b2 mediates muscle weakness associated with bone metastases in mice","volume":"21","author":"Waning","year":"2015","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21352","DOI":"10.1074\/jbc.M111663200","article-title":"Proteolysis of latent transforming growth factor-beta (TGF-beta) binding protein 1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix","volume":"277","author":"Dallas","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1177\/15353702211009213","article-title":"Role of myokines and osteokines in cancer cachexia","volume":"246","author":"Pin","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11021","DOI":"10.1074\/jbc.M116.770941","article-title":"Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microsomal RNA 218: A novel mechanism in muscle-bone communication","volume":"292","author":"Qin","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_14","first-page":"E5266","article-title":"Specific targeting of TGF-\u03b2 family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease","volume":"114","author":"Chen","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/jbmr.3890","article-title":"Zoledronic acid improves muscle function in healthy mice treated with chemotherapy","volume":"35","author":"Hain","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"809","DOI":"10.3389\/fendo.2019.00809","article-title":"Bisphosphonate treatment ameliorates bone and muscle abnormalities in young mice","volume":"10","author":"Essex","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s00198-004-1731-1","article-title":"The efficacy of the acute administration of pamidronate on the conservation of bone mass following severe burn injury in children: A double blind, randomized, controlled study","volume":"16","author":"Klein","year":"2005","journal-title":"Osteoporos. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1002\/jbmr.2162","article-title":"Pamidronate attenuates muscle loss after pediatric burn injury","volume":"29","author":"Borsheim","year":"2014","journal-title":"J. Bone Miner. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"543","DOI":"10.3389\/fendo.2019.00543","article-title":"Molecular mechanisms responsible for the rescue effects of pamidronate on muscle atrophy in pediatric burn patients","volume":"10","author":"Pin","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1097\/SHK.0000000000001393","article-title":"TGF-\u03b2 pathway inhibition protects the diaphragm from sepsis-induced wasting and weakness in rat","volume":"53","author":"Jude","year":"2020","journal-title":"Shock"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nature07034","article-title":"Imbalance between pSmad 3 and Notch induces CDK inhibitors in old muscle stem cells","volume":"454","author":"Carlson","year":"2008","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/jcsm.12414","article-title":"Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age-related muscle wastin","volume":"10","author":"Zhang","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s10157-016-1369-2","article-title":"Management of secondary hyperparathyroidism: How and why?","volume":"21","author":"Komaba","year":"2017","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1002\/ajmg.a.31862","article-title":"Clinical studies in familial VCP myopathy associated with Paget\u2019s disease of bone and frontotemporal dementia","volume":"146","author":"Kimonis","year":"2008","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1002\/jbmr.2200","article-title":"METTL21C is a potential pleiotropic gene for osteoporosis and sarcopenia acting through the modulation of the NF\u03baB signaling pathway","volume":"29","author":"Huang","year":"2014","journal-title":"J. Bone Miner. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"556","DOI":"10.2337\/db18-0416","article-title":"FoxO transcription factors are critical regulators of diabetes-related muscle atrophy","volume":"68","author":"Bhardwaj","year":"2019","journal-title":"Diabetes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.1172\/JCI86522","article-title":"Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis","volume":"126","author":"Lee","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e146415","DOI":"10.1172\/JCI146415","article-title":"Insulin and IGF-1 receptors regulate complex I-dependent bioenergetics and supercomplexes via FoxOs in muscle","volume":"131","author":"Bhardwaj","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"44326","DOI":"10.1074\/jbc.M111.283481","article-title":"Glucocorticoids and tumor necrosis factor alpha increase oxidative stress and suppress Wnt protein signaling in osteoblasts","volume":"286","author":"Almeida","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.cmet.2016.05.004","article-title":"Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise","volume":"23","author":"Mera","year":"2016","journal-title":"Cell Metab."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gugala, Z., Cacciani, N., Klein, G.L., and Larsson, L. (2021). Acute and severe trabecular bone loss in a rat model of critical illness myopathy. J. Orthop. Res.","DOI":"10.1002\/jor.25161"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Llano Diez, M., Gustafson, A.M., Olsson, C., Goransson, H., and Larsson, L. (2011). Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model. BMC Genom., 12.","DOI":"10.1186\/1471-2164-12-602"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"L173","DOI":"10.1152\/ajplung.00083.2014","article-title":"Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation","volume":"307","author":"Zhang","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/2044-5040-1-19","article-title":"Role of TGF-\u03b2 in inherited and acquired myopathies","volume":"1","author":"Burks","year":"2011","journal-title":"Skelet. Muscle"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s12020-012-9751-7","article-title":"Atrogin-1, MuRF-1 and sarcopenia","volume":"43","author":"Gumucio","year":"2013","journal-title":"Endocrine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/S0022-3476(95)70553-8","article-title":"Long-term reduction in bone mass after servere burn inury in children","volume":"126","author":"Klein","year":"1995","journal-title":"J. Pediatr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S2352-4642(17)30122-0","article-title":"Long-term effect of critical illness after severe paediatric burn injury on cardiac function in adolescent survivors: An observational study","volume":"1","author":"Hundeshagen","year":"2017","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1172\/JCI94753","article-title":"Fibroblast specific TGF-\u03b2-Smad 2\/3 signaling underlies cardiac fibrosis","volume":"127","author":"Khalil","year":"2017","journal-title":"J. Clin. Investig."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1167\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:05:23Z","timestamp":1760133923000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1167"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,21]]},"references-count":38,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031167"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031167","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,21]]}}}