Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs.
Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy.
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Rafael
R
Barreto
Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|IUPUI Center for Cachexia Research, Innovation and Therapy, Indianapolis, IN 46202, USA.
David L
DL
Waning
Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Hongyu
H
Gao
Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Yunlong
Y
Liu
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|IUPUI Center for Cachexia Research, Innovation and Therapy, Indianapolis, IN 46202, USA.
Teresa A
TA
Zimmers
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|IUPUI Center for Cachexia Research, Innovation and Therapy, Indianapolis, IN 46202, USA.
Andrea
A
Bonetto
D030301:Activin Receptors, Type II / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001823:Body Composition / Q000187:drug effects; D002100:Cachexia / Q000139:chemically induced / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018763:Muscle Fatigue / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced; D032446:Myoblasts; D055435:Myostatin / Q000037:antagonists & inhibitors; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005419:Flavonoids; C525912:Mstn protein, mouse; D055435:Myostatin; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D002955:Leucovorin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D005472:Fluorouracil; D002166:Camptothecin
MAPKs; cachexia; chemotherapy; mitochondria; muscle wasting