Malnutrition is common in chronic renal failure (CRF) and has adverse effects on morbidity and mortality. Contributing to the malnutrition and muscle wasting is resistance to growth hormone (GH). In uremic children, this resistance impairs growth. Resistance has been attributed to IGF-I insensitivity and theoretically to reduced GH receptor (GHR) levels, while impaired signaling is another potential cause that we recently uncovered in animals. Resistance can be overcome by high doses of GH but does carry some risk of adverse effects. Thus new approaches are needed and this will require a deeper understanding of the mechanism of GH resistance, which is our overall goal.
Specific Aim 1. To evaluate the effect of uremia on GHR levels and GH mediated signal transduction in human skeletal muscle. We propose that in patients with end stage CRF, skeletal muscle resistance to GH is not due to reduced GHR levels, but is caused at least partly, by a defect in GH signal transduction that is worsened by inflammation and malnutrition.
Specific Aim 2. To identify the mechanisms that account for the skeletal muscle resistance to GH induced JAK-STAT signal transduction and IGF-1 gene expression in uremia.
Specific aim 3. To determine whether in uremia there is resistance to a GH independent stimulus of IGF-I gene expression in muscle, namely mechanical overload, or whether resistance is limited to GH induced IGF-I expression.
Specific Aim 4. To establish, a) whether inflammation worsens the resistance to GH signaling and action and, b) whether this is caused by an increase in muscle cytokine expression that together with increased serum cytokines upregulate the suppressors of cytokine signaling. This study carried out in-vitro with human muscle biopsied from normal subjects and patients with end-stage CRF and in-vivo with intact uremic rats, should provide new insight into the mechanism of GH resistance in uremia, including the role of inflammation and malnutrition. In the long run, this information should serve as a basis for developing new strategies to prevent the loss of, or to restore GH sensitivity to GH. If successful, this would allow patients to respond normally to endogenous GH and when required, to low dose recombinant GH, and thus improve the management of muscle wasting in patients with kidney failure. ? ? ?
