title: Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer.
abstract: Recent studies have correlated physical activity with a better prognosis in cachectic patients, although the underlying mechanisms are not yet understood. In order to identify the pathways involved in the physical activity-mediated rescue of skeletal muscle mass and function, we investigated the effects of voluntary exercise on cachexia in colon carcinoma (C26)-bearing mice. Voluntary exercise prevented loss of muscle mass and function, ultimately increasing survival of C26-bearing mice. We found that the autophagic flux is overloaded in skeletal muscle of both colon carcinoma murine models and patients, but not in running C26-bearing mice, thus suggesting that exercise may release the autophagic flux and ultimately rescue muscle homeostasis. Treatment of C26-bearing mice with either AICAR or rapamycin, two drugs that trigger the autophagic flux, also rescued muscle mass and prevented atrogene induction. Similar effects were reproduced on myotubes in vitro, which displayed atrophy following exposure to C26-conditioned medium, a phenomenon that was rescued by AICAR or rapamycin treatment and relies on autophagosome-lysosome fusion (inhibited by chloroquine). Since AICAR, rapamycin and exercise equally affect the autophagic system and counteract cachexia, we believe autophagy-triggering drugs may be exploited to treat cachexia in conditions in which exercise cannot be prescribed.
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Pigna
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Italy.|Department of Kinesiology, Research Group in Exercise Physiology, KU Leuven, Belgium.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Berardi
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Aulino
authors.affiliation: Department of Mechanical &Aerospace Engineering, Sapienza University of Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Rizzuto
authors.affiliation: Department of Biomedical Sciences, University of Padua, Italy.|Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation, Department of Physical Medicine and Rehabilitation, Wilhelminenspital Wien, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zampieri
authors.affiliation: IRCCS Fondazione Ospedale San Camillo, Venezia, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Carraro
authors.affiliation: Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation, Department of Physical Medicine and Rehabilitation, Wilhelminenspital Wien, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Kern
authors.affiliation: Department of Surgical and Gastroenterological Sciences, University of Padua, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Merigliano
authors.affiliation: Department of Surgical and Gastroenterological Sciences, University of Padua, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Gruppo
authors.affiliation: Department of Biological Adaptation and Ageing B2A (CNRS UMR 8256 - INSERM ERL U1164 - UPMC P6), Pierre et Marie Curie University, Paris 6, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Mericskay
authors.affiliation: Department of Biological Adaptation and Ageing B2A (CNRS UMR 8256 - INSERM ERL U1164 - UPMC P6), Pierre et Marie Curie University, Paris 6, France.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biomolecular Sciences, Unit of Biostatistics, "Carlo Bo" University of Urbino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rocchi
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences (BioNeC), University of Palermo, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Barone
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences (BioNeC), University of Palermo, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Macaluso
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences (BioNeC), University of Palermo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Felice
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Adamo
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Italy.|Department of Biological Adaptation and Ageing B2A (CNRS UMR 8256 - INSERM ERL U1164 - UPMC P6), Pierre et Marie Curie University, Paris 6, France.
authors.forename: Dario
authors.initials: D
authors.lastname: Coletti
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Moresi
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002100:Cachexia / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018908:Muscle Weakness / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009368:Neoplasm Transplantation; D010805:Physical Conditioning, Animal; D012265:Ribonucleotides / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology*; D016019:Survival Analysis
chemical_list: D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide; D020123:Sirolimus