Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion
ABSTRACT 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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | JBMR Plus |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jbm4.10804 |
| _version_ | 1797626800132587520 |
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| author | Harshini Suresh Kumar Edwina N. Barnett John L. Fowlkes Evangelia Kalaitzoglou Ramkumar T. Annamalai |
| author_facet | Harshini Suresh Kumar Edwina N. Barnett John L. Fowlkes Evangelia Kalaitzoglou Ramkumar T. Annamalai |
| author_sort | Harshini Suresh Kumar |
| collection | DOAJ |
| description | ABSTRACT 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. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research. |
| first_indexed | 2024-03-11T10:15:21Z |
| format | Article |
| id | doaj.art-0043bdd836294b2ab10875a4a34f03ae |
| institution | Directory Open Access Journal |
| issn | 2473-4039 |
| language | English |
| last_indexed | 2024-03-11T10:15:21Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | JBMR Plus |
| spelling | doaj.art-0043bdd836294b2ab10875a4a34f03ae2023-11-16T09:31:51ZengWileyJBMR Plus2473-40392023-11-01711n/an/a10.1002/jbm4.10804Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine SecretionHarshini Suresh Kumar0Edwina N. Barnett1John L. Fowlkes2Evangelia Kalaitzoglou3Ramkumar T. Annamalai4Department of Biomedical Engineering University of Kentucky Lexington KY USADepartment of Biomedical Engineering University of Kentucky Lexington KY USABarnstable Brown Diabetes Center Lexington KY USABarnstable Brown Diabetes Center Lexington KY USADepartment of Biomedical Engineering University of Kentucky Lexington KY USAABSTRACT 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. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.https://doi.org/10.1002/jbm4.10804BONEDIABETESEXERCISEGELATINMICROGELSMUSCLE |
| spellingShingle | Harshini Suresh Kumar Edwina N. Barnett John L. Fowlkes Evangelia Kalaitzoglou Ramkumar T. Annamalai Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion JBMR Plus BONE DIABETES EXERCISE GELATIN MICROGELS MUSCLE |
| title | Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion |
| title_full | Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion |
| title_fullStr | Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion |
| title_full_unstemmed | Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion |
| title_short | Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion |
| title_sort | biomechanical stimulation of muscle constructs influences phenotype of bone constructs by modulating myokine secretion |
| topic | BONE DIABETES EXERCISE GELATIN MICROGELS MUSCLE |
| url | https://doi.org/10.1002/jbm4.10804 |
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