The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Irinotecan (IRI) Induces Cachexia Which Is Mitigated by BGP-15
2.2. IRI Treatment Causes Muscular Atrophy Which Is Normalized by BGP-15
2.3. IRI Reduces Protein Synthesis which Is Exacerbated by BGP-15
2.4. Assessment of Molecular Markers of Sarcolemmal Membrane Integrity
2.5. Assessment of Skeletal Muscle Contractile Function
2.6. Assessment of Skeletal Muscle Metabolic Phenotype
2.7. Assessment of Redox Balance and Mitochondrial Content Signaling Pathways in Skeletal Muscle
3. Discussion
3.1. Skeletal Muscle Mass versus Protein Synthesis: The Paradoxical Effect of BGP-15 Adjuvant Therapy
3.2. The Relationship between Protein Synthesis and Cytoskeletal Re-Modelling: A Potential Role for Mechanotransduction?
3.3. The Functional Consequence of Cytoskeletal Remodeling by IRI Treatment and BGP-15 Adjuvant Therapy
3.4. BGP-15 Adjuvant Therapy Potentiates Skeletal Muscle Oxidative Metabolism through PARP-1 Inhibition
3.5. Limitations
4. Materials and Methods
4.1. Animals
4.1.1. Ethical Approval
4.1.2. Experimental Design and Treatments
4.2. Body Composition
4.3. Physical Activity Assessment
4.4. Surgery
4.5. Ex Vivo Skeletal Muscle Contractile Function
4.6. Mitochondrial Respiratory Phenotyping
4.6.1. Flexor Digitorum Brevis Muscle Fiber Isolation
4.6.2. Seahorse Microplate Preparation
4.6.3. Mitochondrial Metabolic Profiling Using the XF24 Extracellular Flux Analyzer
4.7. Skeletal Muscle Histology
4.8. Western Blot Analyses
4.9. Citrate Synthase Activity
4.10. Zymography Analyses for Gelatinase Activity
4.11. Statistics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Campelj, D.G.; Timpani, C.A.; Petersen, A.C.; Hayes, A.; Goodman, C.A.; Rybalka, E. The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction. Cancers 2020, 12, 3810. https://doi.org/10.3390/cancers12123810
Campelj DG, Timpani CA, Petersen AC, Hayes A, Goodman CA, Rybalka E. The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction. Cancers. 2020; 12(12):3810. https://doi.org/10.3390/cancers12123810
Chicago/Turabian StyleCampelj, Dean G., Cara A. Timpani, Aaron C. Petersen, Alan Hayes, Craig A. Goodman, and Emma Rybalka. 2020. "The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction" Cancers 12, no. 12: 3810. https://doi.org/10.3390/cancers12123810
APA StyleCampelj, D. G., Timpani, C. A., Petersen, A. C., Hayes, A., Goodman, C. A., & Rybalka, E. (2020). The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction. Cancers, 12(12), 3810. https://doi.org/10.3390/cancers12123810