Modulations of the calcineurin/NF-AT pathway in skeletal muscle atrophy.
Calcineurin has been proposed to regulate skeletal muscle hypertrophy, while its relevance to the pathogenesis of muscle atrophy is unknown. The present study was aimed to investigate if perturbations of the calcineurin pathway may be involved in causing skeletal muscle atrophy in two different experimental conditions: cancer cachexia (rats bearing the AH-130 hepatoma), and hyperglycemia (rats treated with streptozotocin). Calcineurin expression in the gastrocnemius was comparable between tumor hosts and controls. By contrast, besides unchanged calcineurin mRNA levels, those of protein were lower in diabetic animals than in controls. The DNA-binding activity of the transcription factors NF-AT and MEF-2 was analysed as an indirect measure of calcineurin activity in vivo. The nuclear translocation of both factors was similar in tumor hosts and controls. Consistently with the reduced calcineurin protein levels, NF-AT DNA-binding activity significantly decreased in the gastrocnemius of diabetic rats compared to controls. Finally, muscle wasting correction afforded in the AH-130 hosts by pentoxifylline or interleukin-15 was not paralleled by changes of calcineurin mRNA levels, while treatment of diabetic animals with dehydroepiandrosterone partially prevented calcineurin down-regulation. These results suggest that modulations of calcineurin activity may be involved in the pathogenesis of muscle wasting in diabetes though not in cancer cachexia.
Costelli
Paola
P
Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Italy. paolo.costelli@unito.it
Almendro
Vanessa
V
Figueras
Maria Teresa
MT
Reffo
Patrizia
P
Penna
Fabio
F
Aragno
Manuela
M
Mastrocola
Raffaella
R
Boccuzzi
Giuseppe
G
Busquets
Silvia
S
Bonelli
Gabriella
G
Lopez Soriano
Francisco J
FJ
Argilés
Josep M
JM
Baccino
Francesco M
FM
D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000097:blood; D019409:Interleukin-15; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009569:Nitric Oxide / Q000097:blood; D010431:Pentoxifylline; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D007328:Insulin; D019409:Interleukin-15; D050778:NFATC Transcription Factors; D009569:Nitric Oxide; D004247:DNA; D019703:Calcineurin; D010431:Pentoxifylline