title: Cancer cachexia causes skeletal muscle damage via transient receptor potential vanilloid 2-independent mechanisms, unlike muscular dystrophy.
abstract: BACKGROUND
  Muscle wasting during cancer cachexia contributes to patient morbidity. Cachexia-induced muscle damage may be understood by comparing its symptoms with those of other skeletal muscle diseases, but currently available data are limited.
  
  
  METHODS
  We modelled cancer cachexia in mice bearing Lewis lung carcinoma/colon adenocarcinoma and compared the associated muscle damage with that in a murine muscular dystrophy model (mdx mice). We measured biochemical and immunochemical parameters: amounts/localization of cytoskeletal proteins and/or Ca(2+) signalling proteins related to muscle function and abnormality. We analysed intracellular Ca(2+) mobilization and compared results between the two models. Involvement of Ca(2+)-permeable channel transient receptor potential vanilloid 2 (TRPV2) was examined by inoculating Lewis lung carcinoma cells into transgenic mice expressing dominant-negative TRPV2.
  
  
  RESULTS
  Tumourigenesis caused loss of body and skeletal muscle weight and reduced muscle force and locomotor activity. Similar to mdx mice, cachexia muscles exhibited myolysis, reduced sarcolemmal sialic acid content, and enhanced lysosomal exocytosis and sarcolemmal localization of phosphorylated Ca(2+)/CaMKII. Abnormal autophagy and degradation of dystrophin also occurred. Unlike mdx muscles, cachexia muscles did not exhibit regeneration markers (centrally nucleated fibres), and levels of autophagic proteolytic pathway markers increased. While a slight accumulation of TRPV2 was observed in cachexia muscles, Ca(2+) influx via TRPV2 was not elevated in cachexia-associated myotubes, and the course of cachexia pathology was not ameliorated by dominant-negative inhibition of TRPV2.
  
  
  CONCLUSIONS
  Thus, cancer cachexia may induce muscle damage through TRPV2-independent mechanisms distinct from those in muscular dystrophy; this may help treat patients with tumour-induced muscle wasting.
authors.affiliation: Department of Molecular Physiology National Cerebral and Cardiovascular Center Research Institute Suita Osaka 565-8565 Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: Kyowa Hakko Kirin CO. Ltd Chiyoda-ku Tokyo Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Physiology National Cerebral and Cardiovascular Center Research Institute Suita Osaka 565-8565 Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ohtake
authors.affiliation: Department of Molecular Physiology National Cerebral and Cardiovascular Center Research Institute Suita Osaka 565-8565 Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kamauchi
authors.affiliation: Department of Regenerative Medicine, National Institute for Longevity Science National Center for Geriatrics and Gerontology Oobu Aichi 474-8522 Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Viology Division National Cancer Center Research Institute Chuo-ku Tokyo 104-0045 Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Department of Molecular Physiology National Cerebral and Cardiovascular Center Research Institute Suita Osaka 565-8565 Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Wakabayashi
keywords: Cancer cachexia; DGC, dystrophin glycoprotein complex; LLC, Lewis lung carcinoma; Muscular dystrophy; TRPV2, transient receptor potential vanilloid type 2