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The etiology of musculoskeletal complications in such metabolic disorders and the interplay between the muscular and osseous systems are not well understood. Exercise training promises to prevent diabetic myopathy and bone disease and offer protection. Although the muscle\u2010bone interaction is largely biomechanical, the muscle secretome has significant implications for bone biology. Uncoupling effects of biophysical and biochemical stimuli on the adaptive response of bone during exercise training may offer therapeutic targets for diabetic bone disease. Here, we have developed an in vitro model to elucidate the effects of mechanical strain on myokine secretion and its impact on bone metabolism decoupled from physical stimuli. We developed bone constructs using cross\u2010linked gelatin, which facilitated osteogenic differentiation of osteoprogenitor cells. Then muscle constructs were made from fibrin, which enabled myoblast differentiation and myotube formation. We investigated the myokine expression by muscle constructs under strain regimens replicating endurance (END) and high\u2010intensity interval training (HIIT) in hyperglycemic conditions. In monocultures, both regimens induced higher expression of\n                    <jats:italic>Il15<\/jats:italic>\n                    and\n                    <jats:italic>Igf1<\/jats:italic>\n                    , whereas END supported more myoblast differentiation and myotube maturation than HIIT. When co\u2010cultured with bone constructs, HIIT regimen increased\n                    <jats:italic>Glut4<\/jats:italic>\n                    expression in muscle constructs more than END, supporting higher glucose uptake. Likewise, the muscle constructs under the HIIT regimen promoted a healthier and more matured bone phenotype than END. Under static conditions, myostatin (\n                    <jats:italic>Mstn<\/jats:italic>\n                    ) expression was significantly downregulated in muscle constructs co\u2010cultured with bone constructs compared with monocultures. Together, our in vitro co\u2010culture system allowed orthogonal manipulation of mechanical strain on muscle constructs while facilitating bone\u2010muscle biochemical cross\u2010talk. Such systems can provide an individualized microenvironment that allows decoupled biomechanical manipulation, help identify molecular targets, and develop engineered therapies for metabolic bone disease. \u00a9 2023 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10804","type":"journal-article","created":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T04:49:52Z","timestamp":1692074992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion"],"prefix":"10.1093","volume":"7","author":[{"given":"Harshini","family":"Suresh Kumar","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering 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