Skeletal muscle wasting in tumor-bearing rats is associated with MyoD down-regulation.
Cachexia is a syndrome characterized by profound skeletal muscle wasting that frequently complicates malignancies. A number of studies indicate that protein hypercatabolism, largely mediated by classical hormones and cytokines, is the major component of muscle depletion. Impaired regeneration has been suggested to contribute to the reduction of muscle size. In particular, it has been shown that the expression of MyoD, a muscle-specific transcription factor, is down-regulated by cytokines such as TNFalpha and IFNgamma in a NF-kappaB-dependent posttranscriptional manner. The present study investigated whether modulations of the transcription factor MyoD are associated with the onset of muscle wasting in a well established model of cancer cachexia. Rats bearing the Yoshida AH-130 hepatoma develop a condition of muscle protein hypercatabolism, largely dependent on TNFalpha bioactivity. In the gastrocnemius of these animals the expression of MyoD was markedly reduced, paralleling the decrease of muscle weight. This pattern is associated with increased nuclear translocation of AP-1, while DNA-binding assays did not detect any change in NF-kappaB activity. This is the first observation demonstrating that muscle depletion in tumor-bearing rats is associated with a down-regulation of MyoD levels. Although the underlying mechanisms remain to be clarified, this change is compatible with the hypothesis that a reduced expression of molecules involved in the regulation of the regenerative response may concur to muscle wasting in cancer cachexia.
Costelli
P
P
Dipartimento di Medicina ed Oncologia Sperimentale, Universitá di Torino, I-10125 Torino, Italy. paola.costelli@unito.it
Muscaritoli
M
M
Bossola
M
M
Moore-Carrasco
R
R
Crepaldi
S
S
Grieco
G
G
Autelli
R
R
Bonelli
G
G
Pacelli
F
F
Lopez-Soriano
F J
FJ
Argilés
J M
JM
Doglietto
G B
GB
Baccino
F M
FM
Rossi Fanelli
F
F
D000818:Animals; D002100:Cachexia / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D017570:MyoD Protein / Q000032:analysis*; D009374:Neoplasms, Experimental / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019282:Wasting Syndrome / Q000209:etiology* / Q000378:metabolism
D017570:MyoD Protein; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D004247:DNA