GTS-21 attenuates loss of body mass, muscle mass, and function in rats having systemic inflammation with and without disuse atrophy
Muscle changes of critical illness are attributed to systemic inflammatory responses and disuse atrophy. GTS-21 (3-(2,4-dimethoxy-benzylidene)anabaseine), also known as DMBX-A) is a synthetic derivative of the natural product anabaseine that acts as an agonist at α7-acetylcholine receptors (α7nAChRs). Hypothesis tested was that modulation of inflammation by agonist GTS-21 (10 mg/kg b.i.d. intraperitoneally) will attenuate body weight (BW) and muscle changes. Systemic sham inflammation was produced in 125 rats by Cornyebacterium parvum (C.p.) or saline injection on days 0/4/8. Seventy-four rats had one immobilized-limb producing disuse atrophy. GTS-21 effects on BW, tibialis muscle mass (TMM), and function were assessed on day 12. Systemically, methemoglobin levels increased 26-fold with C.p. (p < 0.001) and decreased significantly (p < 0.033) with GTS-21. Control BW increased (+ 30 ± 9 g, mean ± SD) at day 12, but decreased with C.p. and superimposed disuse (p = 0.005). GTS-21 attenuated BW loss in C.p. (p = 0.005). Compared to controls, TMM decreased with C.p. (0.43 ± 0.06 g to 0.26 ± 0.03 g) and with superimposed disuse (0.18 ± 0.04 g); GTS-21 ameliorated TMM loss to 0.32 ± 0.04 (no disuse, p = 0.028) and to 0.22 ± 0.03 (with disuse, p = 0.004). Tetanic tensions decreased with C.p. or disuse and GTS-21 attenuated tension decrease in animals with disuse (p = 0.006) and in animals with C.p. and disuse (p = 0.029). C.p.-induced 11-fold increased muscle α7nAChR expression was decreased by > 60% with GTS-21 treatment. In conclusion, GTS-21 modulates systemic inflammation, evidenced by both decreased methemoglobin levels and decrease of α7nAChR expression, and mitigates inflammation-mediated loss of BW, TMM, fiber size, and function.
Keywords3-(2,4-dimethoxybenzylidene)anabaseine Critical care DMXB Muscular disorders Atrophic Muscle weakness
The authors would like to thank Univ. Prof. Dr. med., Dipl.-Phys. Eberhard Kochs for his continued scientific advice and support and the following collaborators for their technical assistance: Sandra Baur, Andreas Blaschke, Nina Bayer, Anna Folz, Eva Nuspl (all from Klinikum rechts der Isar, Technical University of Munich, Germany).
Support in Munich, Germany, was provided solely from institutional and/or departmental sources. Jeevendra Martyn was supported in part by grants from the National Institutes of Health, Bethesda, MD (P50-GM21500, Project I, and RO1-GM 118947) and grants from Shriners Hospitals for Children®—Tampa, FL.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Research involving animals
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This animal study was approved by the institutional review board (Subcommittee on Research Animal Care, Committee on Research, Massachusetts General Hospital, #2010N000168).
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