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Glycogen Synthase Kinase-3β Inhibitor Lithium Chloride Protects Against Inflammation-Mediated Skeletal Muscle Wasting
Darren Williams
Gwangju Institute of Science and Technology
Corresponding Author
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Inflammation-mediated skeletal muscle wasting is induced by inflammatory cytokines. It occurs in critically ill patients with sepsis (termed intensive care unit acquired weakness) and patients with advanced metastasis (termed cancer cachexia). Both conditions severely impact on patient morbidity and mortality. Lithium chloride has been investigated as a drug repurposing candidate for numerous diseases. In this study, we assessed whether lithium chloride affects inflammation-mediated muscle wasting, using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell conditioned media, maintained expression of the muscle fiber contractile protein, myosin heavy chain 2 and blocked upregulation of the E3 ubiquitin ligase, Atrogin-1. Glycogen synthase kinase-3β inhibition was indicated as the target mechanism, due to the following observations: 1) β-catenin was upregulated in the myotubes and 2) inhibition of IMPA1, the secondary biological target of lithium chloride, did not inhibit the effects of cancer conditioned media. Lithium chloride inhibited upregulation of the inflammation-associated cytokines Il-1β, Il-6 and inos in macrophages treated with lipopolysaccharide. Lithium chloride treatment in an animal model of sepsis improved body weight, increased muscle mass, preserved the survival of larger fibers and decreased expression of the wasting effector genes, Atrogin-1 and Murf-1. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength and increased fiber cross sectional area, with no significant effect on tumorigenesis. These results indicate that lithium chloride could be repurposed as a drug to treat patients with inflammation-mediated skeletal muscle wasting.
Keywords
cancer cachexia, intensive care unit acquired weakness, skeletal muscle wasting, lithium chloride, glycogen synthase kinase-3β, sepsis
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Glycogen Synthase Kinase-3β Inhibitor Lithium Chloride Protects Against Inflammation-Mediated Skeletal Muscle Wasting
Darren Williams
Gwangju Institute of Science and Technology
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 04 Jan, 2021
No community comments so far
Editorial decision: Major revision
On 21 Jan, 2021
Review #4 received
Received 17 Jan, 2021
Review #1 received
Received 17 Jan, 2021
Review #3 received
Received 17 Jan, 2021
Review #5 received
Received 17 Jan, 2021
Review #2 received
Received 17 Jan, 2021
Reviewer #7 agreed
On 12 Jan, 2021
Reviewer #4 agreed
On 12 Jan, 2021
Reviewer #6 agreed
On 12 Jan, 2021
Reviewer #3 agreed
On 12 Jan, 2021
Reviewer #5 agreed
On 12 Jan, 2021
Reviewer #16 agreed
On 11 Jan, 2021
Reviewer #10 agreed
On 11 Jan, 2021
Reviewer #8 agreed
On 11 Jan, 2021
Reviewer #1 agreed
On 11 Jan, 2021
Reviewer #2 agreed
On 11 Jan, 2021
Reviewer #13 agreed
On 11 Jan, 2021
Reviewer #15 agreed
On 11 Jan, 2021
Reviewer #12 agreed
On 11 Jan, 2021
Reviewer #17 agreed
On 11 Jan, 2021
Reviewer #11 agreed
On 11 Jan, 2021
Reviewer #14 agreed
On 11 Jan, 2021
Reviewer #9 agreed
On 11 Jan, 2021
Reviewers invited
Invitations sent on 05 Jan, 2021
Editor assigned
On 05 Jan, 2021
Editor invited
On 30 Dec, 2020
Submission checks complete
On 30 Dec, 2020
First submitted
On 22 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Nanoscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Inflammation-mediated skeletal muscle wasting is induced by inflammatory cytokines. It occurs in critically ill patients with sepsis (termed intensive care unit acquired weakness) and patients with advanced metastasis (termed cancer cachexia). Both conditions severely impact on patient morbidity and mortality. Lithium chloride has been investigated as a drug repurposing candidate for numerous diseases. In this study, we assessed whether lithium chloride affects inflammation-mediated muscle wasting, using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell conditioned media, maintained expression of the muscle fiber contractile protein, myosin heavy chain 2 and blocked upregulation of the E3 ubiquitin ligase, Atrogin-1. Glycogen synthase kinase-3β inhibition was indicated as the target mechanism, due to the following observations: 1) β-catenin was upregulated in the myotubes and 2) inhibition of IMPA1, the secondary biological target of lithium chloride, did not inhibit the effects of cancer conditioned media. Lithium chloride inhibited upregulation of the inflammation-associated cytokines Il-1β, Il-6 and inos in macrophages treated with lipopolysaccharide. Lithium chloride treatment in an animal model of sepsis improved body weight, increased muscle mass, preserved the survival of larger fibers and decreased expression of the wasting effector genes, Atrogin-1 and Murf-1. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength and increased fiber cross sectional area, with no significant effect on tumorigenesis. These results indicate that lithium chloride could be repurposed as a drug to treat patients with inflammation-mediated skeletal muscle wasting.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7