Human adaptation to immobilization: Novel insights of impacts on glucose disposal and fuel utilization

Natalie F. Shur, Elizabeth J. Simpson, Hannah Crossland, Prince K. Chivaka, Despina Constantin, Sally M. Cordon, Dumitru Constantin-Teodosiu, Francis B. Stephens, Dileep N. Lobo, Nate Szewczyk, Marco Narici, Clara Prats, Ian A. Macdonald, Paul L. Greenhaff*

*Corresponding author af dette arbejde

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Abstract

Background: Bed rest (BR) reduces whole-body insulin-stimulated glucose disposal (GD) and alters muscle fuel metabolism, but little is known about metabolic adaptation from acute to chronic BR nor the mechanisms involved, particularly when volunteers are maintained in energy balance. Methods: Healthy males (n = 10, 24.0 ± 1.3 years), maintained in energy balance, underwent 3-day BR (acute BR). A second cohort matched for sex and body mass index (n = 20, 34.2 ± 1.8 years) underwent 56-day BR (chronic BR). A hyperinsulinaemic euglycaemic clamp (60 mU/m2/min) was performed to determine rates of whole-body insulin-stimulated GD before and after BR (normalized to lean body mass). Indirect calorimetry was performed before and during steady state of each clamp to calculate rates of whole-body fuel oxidation. Muscle biopsies were taken to determine muscle glycogen, metabolite and intramyocellular lipid (IMCL) contents, and the expression of 191 mRNA targets before and after BR. Two-way repeated measures analysis of variance was used to detect differences in endpoint measures. Results: Acute BR reduced insulin-mediated GD (Pre 11.5 ± 0.7 vs. Post 9.3 ± 0.6 mg/kg/min, P < 0.001), which was unchanged in magnitude following chronic BR (Pre 10.2 ± 0.4 vs. Post 7.9 ± 0.3 mg/kg/min, P < 0.05). This reduction in GD was paralleled by the elimination of the 35% increase in insulin-stimulated muscle glycogen storage following both acute and chronic BR. Acute BR had no impact on insulin-stimulated carbohydrate (CHO; Pre 3.69 ± 0.39 vs. Post 4.34 ± 0.22 mg/kg/min) and lipid (Pre 1.13 ± 0.14 vs. Post 0.59 ± 0.11 mg/kg/min) oxidation, but chronic BR reduced CHO oxidation (Pre 3.34 ± 0.18 vs. Post 2.72 ± 0.13 mg/kg/min, P < 0.05) and blunted the magnitude of insulin-mediated inhibition of lipid oxidation (Pre 0.60 ± 0.07 vs. Post 0.85 ± 0.06 mg/kg/min, P < 0.05). Neither acute nor chronic BR increased muscle IMCL content. Plentiful mRNA abundance changes were detected following acute BR, which waned following chronic BR and reflected changes in fuel oxidation and muscle glycogen storage at this time point. Conclusions: Acute BR suppressed insulin-stimulated GD and storage, but the extent of this suppression increased no further in chronic BR. However, insulin-mediated inhibition of fat oxidation after chronic BR was less than acute BR and was accompanied by blunted CHO oxidation. The juxtaposition of these responses shows that the regulation of GD and storage can be dissociated from substrate oxidation. Additionally, the shift in substrate oxidation after chronic BR was not explained by IMCL accumulation but reflected by muscle mRNA and pyruvate dehydrogenase kinase 4 protein abundance changes, pointing to lack of muscle contraction per se as the primary signal for muscle adaptation.

OriginalsprogEngelsk
TidsskriftJournal of Cachexia, Sarcopenia and Muscle
Vol/bind13
Udgave nummer6
Sider (fra-til)2999-3013
ISSN2190-5991
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
This study was supported by the Biotechnology and Biological Sciences Research Council (BB/P005004/1), a European Society for Clinical Nutrition and Metabolism (ESPEN) research fellowship awarded to Natalie F. Shur and the NIHR Nottingham Biomedical Research Centre. The chronic bed‐rest study detailed in this manuscript was sponsored by the European Space Agency (ESA).

Funding Information:
This study was supported by the Biotechnology and Biological Sciences Research Council (BB/P005004/1), a European Society for Clinical Nutrition and Metabolism (ESPEN) research fellowship awarded to Natalie F. Shur and the NIHR Nottingham Biomedical Research Centre. The chronic bed-rest study detailed in this manuscript was sponsored by the European Space Agency (ESA). We very much thank all the participants who took part in the studies. We also gratefully acknowledge the staff at the Institute for Space Medicine and Physiology (MEDES) in Toulouse for their organization and running of the chronic bed-rest study, in particular Marie-Pierre Bareille and Arnaud Beck, and Dr Joanne Mallinson and Dr Martino Franchi for the handling of blood and muscle samples in Toulouse. We would also like to thank all the staff at the David Greenfield Human Physiology Unit, University of Nottingham, including the bank staff, who supported the acute bed-rest study. The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle.

Publisher Copyright:
© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

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