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Glucose Uptake and Insulin Response in Tissue-engineered Human Skeletal Muscle

Tissue Engineering and Regenerative Medicine 2020년 17권 6호 p.801 ~ 813
Kondash Megan E., Ananthakumar Anandita, Khodabukus Alastair, Bursac Nenad, Truskey George A.,
소속 상세정보
 ( Kondash Megan E. ) - Duke University Department of Biomedical Engineering
 ( Ananthakumar Anandita ) - Duke University Department of Biomedical Engineering
 ( Khodabukus Alastair ) - Duke University Department of Biomedical Engineering
 ( Bursac Nenad ) - Duke University Department of Biomedical Engineering
 ( Truskey George A. ) - Duke University Department of Biomedical Engineering

Abstract


Background: Tissue-engineered muscles (“myobundles”) offer a promising platform for developing a human in vitro model of healthy and diseased muscle for drug development and testing. Compared to traditional monolayer cultures, myobundles better model the three-dimensional structure of native skeletal muscle and are amenable to diverse functional measures to monitor the muscle health and drug response. Characterizing the metabolic function of human myobundles is of particular interest to enable their utilization in mechanistic studies of human metabolic diseases, identification of related drug targets, and systematic studies of drug safety and efficacy.

Methods: To this end, we studied glucose uptake and insulin responsiveness in human tissue-engineered skeletal muscle myobundles in the basal state and in response to drug treatments.

Results: In the human skeletal muscle myobundle system, insulin stimulates a 50% increase in 2-deoxyglucose (2-DG) uptake with a compiled EC50 of 0.27?±?0.03 nM. Treatment of myobundles with 400 μM metformin increased basal 2-DG uptake 1.7-fold and caused a significant drop in twitch and tetanus contractile force along with decreased fatigue resistance. Treatment with the histone deacetylase inhibitor 4-phenylbutyrate (4-PBA) increased the magnitude of insulin response from a 1.2-fold increase in glucose uptake in the untreated state to a 1.4-fold increase after 4-PBA treatment. 4-PBA treated myobundles also exhibited increased fatigue resistance and increased twitch half-relaxation time.

Conclusion: Although tissue-engineered human myobundles exhibit a modest increase in glucose uptake in response to insulin, they recapitulate key features of in vivo insulin sensitivity and exhibit relevant drug-mediated perturbations in contractile function and glucose metabolism.

키워드

Tissue engineering; Muscle; Skeletal; Insulin; Myobundles

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