Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion

Harshini Suresh Kumar, Edwina N. Barnett, John L. Fowlkes, Evangelia Kalaitzoglou, Ramkumar T. Annamalai

Research output: Contribution to journalArticlepeer-review


Diabetes is a chronic metabolic disorder that can lead to diabetic myopathy and bone diseases. 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-bone 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-linked 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-intensity interval training (HIIT) in hyperglycemic conditions. In monocultures, both regimens induced higher expression of Il15 and Igf1, whereas END supported more myoblast differentiation and myotube maturation than HIIT. When co-cultured with bone constructs, HIIT regimen increased Glut4 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 (Mstn) expression was significantly downregulated in muscle constructs co-cultured with bone constructs compared with monocultures. Together, our in vitro co-culture system allowed orthogonal manipulation of mechanical strain on muscle constructs while facilitating bone-muscle biochemical cross-talk. Such systems can provide an individualized microenvironment that allows decoupled biomechanical manipulation, help identify molecular targets, and develop engineered therapies for metabolic bone disease.

Original languageEnglish
JournalJBMR Plus
StateAccepted/In press - 2023

Bibliographical note

Funding Information:
Research reported in this publication was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) award number R21AR078447, National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health under award numbers P20GM130456 and P20GM103436‐20 (KY IDeA Networks of Biomedical Research Excellence), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) award number K08DK124566, Igniting Research Collaborations program funded by the University of Kentucky Vice President for Research and College Deans, and Orthopedic Trauma Association (OTA; grant number 6889). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other grant funding agencies.

Publisher Copyright:
© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.


  • BONE

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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