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Article

Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy

1
Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 1307 Dresden, Germany
2
Dresden Cardiovascular Research Institute and Core Laboratories GmbH, 01067 Dresden, Germany
3
Department of Drug Research, Enamine-Bienta Ltd., 02000 Kiev, Ukraine
4
Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
5
Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2020, 9(10), 2272; https://doi.org/10.3390/cells9102272
Received: 4 September 2020 / Revised: 17 September 2020 / Accepted: 21 September 2020 / Published: 11 October 2020
(This article belongs to the Special Issue Skeletal Muscle Atrophy: Mechanisms at a Cellular Level)
Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available for CaCax. Here, we studied skeletal muscle atrophy and dysfunction in a murine CaCax model by injecting B16F10 melanoma cells into mouse thighs and followed mice during melanoma outgrowth. Skeletal muscles developed progressive weakness as detected by wire hang tests (WHTs) during days 13–23. Individual muscles analyzed at day 24 had atrophy, mitochondrial dysfunction, augmented metabolic reactive oxygen species (ROS) stress, and a catabolically activated ubiquitin proteasome system (UPS), including upregulated MuRF1. Accordingly, we tested as an experimental intervention of recently identified small molecules, Myomed-205 and -946, that inhibit MuRF1 activity and MuRF1/MuRF2 expression. Results indicate that MuRF1 inhibitor fed attenuated induction of MuRF1 in tumor stressed muscles. In addition, the compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed-205 and -946 also rescued citrate synthase and complex-1 activities in tumor-stressed muscles, possibly suggesting that mitochondrial-metabolic and muscle wasting effects in this CaCax model are mechanistically connected. Inhibition of MuRF1 during tumor cachexia may represent a suitable strategy to attenuate skeletal muscle atrophy and dysfunction. View Full-Text
Keywords: cancer cachexia; melanoma tumors; muscle wasting; mitochondrial metabolism; MuRF1; chemical biology cancer cachexia; melanoma tumors; muscle wasting; mitochondrial metabolism; MuRF1; chemical biology
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MDPI and ACS Style

Adams, V.; Gußen, V.; Zozulya, S.; Cruz, A.; Moriscot, A.; Linke, A.; Labeit, S. Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy. Cells 2020, 9, 2272. https://doi.org/10.3390/cells9102272

AMA Style

Adams V, Gußen V, Zozulya S, Cruz A, Moriscot A, Linke A, Labeit S. Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy. Cells. 2020; 9(10):2272. https://doi.org/10.3390/cells9102272

Chicago/Turabian Style

Adams, Volker, Victoria Gußen, Sergey Zozulya, André Cruz, Anselmo Moriscot, Axel Linke, and Siegfried Labeit. 2020. "Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy" Cells 9, no. 10: 2272. https://doi.org/10.3390/cells9102272

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