Chronic uremia attenuates growth hormone-induced signal transduction in skeletal muscle.
Malnutrition and muscle wasting are common in chronic renal failure (CRF) and adversely affect morbidity and mortality. Contributing to the muscle wasting is resistance to growth hormone (GH). For testing whether impaired GH signaling is a cause of the skeletal muscle GH resistance and for elucidating its mechanisms, muscle GH signaling and action were studied in GH-deficient rats with surgically induced CRF and sham-operated pairfed control rats. GH treatment increased gastrocnemius muscle IGF-1 mRNA levels significantly in control but not in CRF rats. GH-activated Janus-associated kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) signaling was impaired in CRF rats, despite normal GH receptor (GHR), JAK2, and STAT5 protein levels. Phosphorylation of the GHR, JAK2, and STAT5 in response to GH was depressed by nearly half in CRF (P < 0.05), and nuclear phospho-STAT5 levels were depressed by approximately one third (P < 0.01). GH-stimulated suppressors of cytokine signaling 2 mRNA levels were significantly higher in CRF. This may be related to inflammatory cytokine activity because C-reactive protein levels were elevated. Muscle protein-tyrosine phosphatase activity was also increased significantly by twofold. In conclusion, rats with CRF acquire skeletal muscle resistance to GH that is caused at least in part by impaired JAK2-GHR-STAT5 phosphorylation and nuclear STAT5 translocation. Furthermore, it seems that the attenuated JAK2-STAT5 phosphorylation may be caused by at least two different processes. One involves depressed phosphorylation of the signaling proteins because of increased suppressors of cytokine signaling 2 expression that may be linked to low-grade inflammation. The other may involve increased signaling protein dephosphorylation because of heightened protein-tyrosine phosphatase activity.
Veterans Affairs Palo Alto Health Care System, CA 94304, USA.
Di Fei
DF
Sun
Zhilan
Z
Zheng
Padmaja
P
Tummala
Jun
J
Oh
Franz
F
Schaefer
Ralph
R
Rabkin
D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D004351:Drug Resistance; D013006:Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D053614:Janus Kinase 2; D007676:Kidney Failure, Chronic / Q000150:complications / Q000503:physiopathology; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009392:Nephrectomy; D016133:Polymerase Chain Reaction; D011336:Probability; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D014511:Uremia / Q000150:complications / Q000503:physiopathology*
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2