Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition.
BACKGROUND
The onset of cachexia is a frequent feature in cancer patients. Prominent characteristic of this syndrome is the loss of body and muscle weight, this latter being mainly supported by increased protein breakdown rates. While the signaling pathways dependent on IGF-1 or myostatin were causally involved in muscle atrophy, the role of the Mitogen-Activated-Protein-Kinases is still largely debated. The present study investigated this point on mice bearing the C26 colon adenocarcinoma.


RESULTS
C26-bearing mice display a marked loss of body weight and muscle mass, this latter associated with increased phosphorylated (p)-ERK. Administration of the ERK inhibitor PD98059 to tumor bearers attenuates muscle depletion and weakness, while restoring normal atrogin-1 expression. In C26 hosts, muscle wasting is also associated with increased Pax7 expression and reduced myogenin levels. Such pattern, suggestive of impaired myogenesis, is reversed by PD98059. Increased p-ERK and reduced myosin heavy chain content can be observed in TNFα-treated C2C12 myotubes, while decreased myogenin and MyoD levels occur in differentiating myoblasts exposed to the cytokine. All these changes are prevented by PD98059.


CONCLUSIONS
These results demonstrate that ERK is involved in the pathogenesis of muscle wasting in cancer cachexia and could thus be proposed as a therapeutic target.
Department of Experimental Medicine and Oncology, University of Torino, Torino, Italy.
Fabio
F
Penna
Domiziana
D
Costamagna
Alessandro
A
Fanzani
Gabriella
G
Bonelli
Francesco M
FM
Baccino
Paola
P
Costelli
D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005419:Flavonoids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000473:pathology*; D009929:Organ Size; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one