title: Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.
abstract: Cachexia is a devastating syndrome that causes morbidity and mortality in a large number of patients with cancer. However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress. The ER responds to this stress through activating certain pathways commonly known as the unfolding protein response (UPR). The main function of UPR is to restore homeostasis, but excessive or prolonged activation of UPR can lead to pathologic conditions. In this study, we examined the role of ER stress and UPR in regulation of skeletal muscle mass in naïve conditions and during cancer cachexia. Our results demonstrate that multiple markers of ER stress are highly activated in skeletal muscle of Lewis lung carcinoma (LLC) and Apc(Min/+) mouse models of cancer cachexia. Treatment of mice with 4-phenylbutyrate (4-PBA), a chemical chaperon and a potent inhibitor of ER stress, significantly reduced skeletal muscle strength and mass in both control and LLC-bearing mice. Blocking the UPR also increased the proportion of fast-type fibers in soleus muscle of both control and LLC-bearing mice. Inhibition of UPR reduced the activity of Akt/mTOR pathway and increased the expression of the components of the ubiquitin-proteasome system and autophagy in LLC-bearing mice. Moreover, we found that the inhibition of UPR causes severe atrophy in cultured myotubes. Our study provides initial evidence that ER stress and UPR pathways are essential for maintaining skeletal muscle mass and strength and for protection against cancer cachexia.-Bohnert, K. R., Gallot, Y. S., Sato, S., Xiong, G., Hindi, S. M., Kumar, A. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Bohnert
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Yann S
authors.initials: YS
authors.lastname: Gallot
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Guangyan
authors.initials: G
authors.lastname: Xiong
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Sajedah M
authors.initials: SM
authors.lastname: Hindi
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA ashok.kumar@louisville.edu.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002100:Cachexia / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal; D009133:Muscular Atrophy / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010654:Phenylbutyrates / Q000633:toxicity; D058767:Protein Unfolding; D051057:Proto-Oncogene Proteins c-akt; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D051702:Activating Transcription Factor 6; D025601:Adenomatous Polyposis Coli Protein; C497112:Atf6 protein, mouse; D015415:Biomarkers; D010654:Phenylbutyrates; C000613192:adenomatous polyposis coli protein, mouse; C075773:4-phenylbutyric acid; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: Lewis lung carcinoma; PERK; XBP-1; autophagy; mTOR