title: Altered cardiac muscle mTOR regulation during the progression of cancer cachexia in the ApcMin/+ mouse.
abstract: Cancer cachexia is a muscle wasting condition that occurs in response to a malignant growth in the body. The mechanisms regulating cardiac muscle mass with cachexia are not well understood. Using the ApcMin/+ mouse model of colorectal cancer, we investigated how cachexia affects the regulation of 5'-adenosine monophosphate-activated protein kinase (AMPK), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling in the heart. Compared to age-matched C57BL/6 (BL6) mice, ApcMin/+ body mass and heart mass were lower at 12 (11 ± 5 and 8 ± 3%, respectively) and 20 weeks (26 ± 3 and 6 ± 4%, respectively) of age (P<0.05). Diminished heart mass in the 20-week-old ApcMin/+ mice coincided with a decreased rate of myofibrillar protein synthesis and increased AMPKα phosphorylation. Cachexia decreased mTOR phosphorylation and the phosphorylation of the mTOR substrates, S6 ribosomal protein and 4EBP1 independent of Akt activation. These changes in mTOR-related protein signaling were accompanied by modest increases in the amount of Beclin1 but not protein ubiquitination or cardiomyocyte apoptosis. Taken together, these data suggest that loss of cardiac mass during cachexia progression in the ApcMin/+ mouse is associated with an Akt-independent suppression of anabolic signaling and evidence of increased autophagy.
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755-1090, USA.
authors.forename: Nandini D P K
authors.initials: ND
authors.lastname: Manne
authors.forename: M
authors.initials: M
authors.lastname: Lima
authors.forename: R T
authors.initials: RT
authors.lastname: Enos
authors.forename: P
authors.initials: P
authors.lastname: Wehner
authors.forename: J A
authors.initials: JA
authors.lastname: Carson
authors.forename: Eric
authors.initials: E
authors.lastname: Blough
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000071186:Beclin-1; D002100:Cachexia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D015179:Colorectal Neoplasms / Q000150:complications / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D039642:Eukaryotic Initiation Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009369:Neoplasms / Q000150:complications* / Q000378:metabolism; D009929:Organ Size; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D054875:Ubiquitination; D015431:Weight Loss
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases