Flight and Jump muscles respond differently to experimental cachexia and impaired insulin signaling.
Disciplines
Animal Experimentation and Research | Cancer Biology | Developmental Biology | Molecular Genetics
Abstract (300 words maximum)
Cancer cachexia is a metabolic syndrome characterized by progressive wasting of muscle tissue in the presence of a tumor. In many cases, progressive muscle wasting becomes a primary cause of mortality in cancer patients, although molecular mechanisms of such phenomenon are not fully understood. In this study, we assessed cachexia sensitivity in the two largest but otherwise highly distinct types of muscle fibers belonging to indirect flight muscles (IFMs) and jump muscles (TDT).
Using a previously established model, we induced cachexia in adult flies by expressing a mutated transcriptional activator yorkie (yki) via the esg driver, in the midgut. Cachectic esg>yki flies progressively lost flight ability within two weeks after midgut neoplasia induction (82% flight-impaired flies), which suggested dysfunctional IFMs. Accordingly, succinate dehydrogenase (SDH) activity assay revealed reduced mitochondrial activity in 35% of IFM fibers in esg>yki flies, while 10% of IFM fibers were completely degenerated and lacked any SDH activity. We recapitulated the cachectic phenotype, without midgut neoplasia, in IFMs overexpressing a dominant-negative insulin receptor (100% flight-impaired flies, 11% degenerated IFM fibers at 2 weeks). In contrast to IFM data, TDT muscles did not demonstrate exacerbated fiber degeneration or significant functional decline (retaining 80% of jumping power and 100% of live fibers at 2 weeks) in esg>yki flies.
Our results indicate that muscles with high energetic expenditures, like IFMs, become most vulnerable to insulin signaling perturbations caused by collateral tumors. The comparative model of IFM and TDT muscles may reveal genetic factors that determine the difference in cachectic response.
Academic department under which the project should be listed
CSM - Molecular and Cellular Biology
Primary Investigator (PI) Name
Anton Bryantsev
Flight and Jump muscles respond differently to experimental cachexia and impaired insulin signaling.
Cancer cachexia is a metabolic syndrome characterized by progressive wasting of muscle tissue in the presence of a tumor. In many cases, progressive muscle wasting becomes a primary cause of mortality in cancer patients, although molecular mechanisms of such phenomenon are not fully understood. In this study, we assessed cachexia sensitivity in the two largest but otherwise highly distinct types of muscle fibers belonging to indirect flight muscles (IFMs) and jump muscles (TDT).
Using a previously established model, we induced cachexia in adult flies by expressing a mutated transcriptional activator yorkie (yki) via the esg driver, in the midgut. Cachectic esg>yki flies progressively lost flight ability within two weeks after midgut neoplasia induction (82% flight-impaired flies), which suggested dysfunctional IFMs. Accordingly, succinate dehydrogenase (SDH) activity assay revealed reduced mitochondrial activity in 35% of IFM fibers in esg>yki flies, while 10% of IFM fibers were completely degenerated and lacked any SDH activity. We recapitulated the cachectic phenotype, without midgut neoplasia, in IFMs overexpressing a dominant-negative insulin receptor (100% flight-impaired flies, 11% degenerated IFM fibers at 2 weeks). In contrast to IFM data, TDT muscles did not demonstrate exacerbated fiber degeneration or significant functional decline (retaining 80% of jumping power and 100% of live fibers at 2 weeks) in esg>yki flies.
Our results indicate that muscles with high energetic expenditures, like IFMs, become most vulnerable to insulin signaling perturbations caused by collateral tumors. The comparative model of IFM and TDT muscles may reveal genetic factors that determine the difference in cachectic response.