Muscle gp130 Receptor Regulation of Oxidative Metabolism During Cancer Cachexia
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IntroductionMuscle oxidative metabolism is disrupted by the cachectic environment brought on by cancer. Processes related to mitochondrial biogenesis, dynamics, and mitophagy are all altered. The IL6 family of cytokines have an established regulatory role in cachectic signaling in several preclinical mouse models through the activation of intracellular signaling pathways initiated by receptor complexes involving glycoprotein 130 (gp130). Therefore, we examined muscle gp130 role in the disruption of muscle oxidative metabolism induced by a cachectic environment.MethodsMale, C57BL/6 (B6, N=5), ApcMin/+ (MIN; N=5), skeletal muscle specific gp130 knockout (KO; N=5), ApcMin/+ KO (MIN KO; N=5) mice were sacrificed at 20 weeks of age. Additionally, Lewis Lung Carcinoma (LLC) injected B6 (N=5) and KO (N=5) mice were examined 30 days after injection. C2C12 myotubes were treated with a small molecule STAT3 inhibitor (C1889) and incubated in LLC conditioned media (24 hours). Oxidative metabolism, mitochondrial content, and dynamics were examined.ResultsLLC and MIN increased muscle gp130 protein expression and STAT3, which was suppressed by gp130 KO. COX activity was decreased in LLC and MIN, and not rescued by the KO. MIN and LLC increased FIS1 protein expression, and this induction was ablated by KO in both mice. MIN decreased MFN1 protein expression which was not altered by KO. Beclin1 and 4HNE protein expression increased in MIN and LLC, and the KO blocked this induction. LLC media activation of myotube STAT3 was blocked using the C1889 inhibitor. Inhibiting the LLC induction of STAT3 in cultured myotubes did not affect the induction if FIS1, Beclin1 and 4HNE protein expression.ConclusionsThese results implicate direct signaling through the muscle gp130 receptor for the cachexia regulation of muscle mitochondrial dynamics and autophagy, and this regulation may be independent of STAT3.Support or Funding InformationThis work was supported by National Institutes of Health grant # NCIR01CA121249 (JAC)
