Resistance to growth hormone (GH)-induced insulin-like growth factor-1 (IGF-1) gene expression contributes to uremic muscle wasting. Since exercise stimulates muscle IGF-1 expression independent of GH, we tested whether work overload (WO) could increase skeletal muscle IGF-1 expression in uremia and thus bypass the defective GH action. Furthermore, to provide insight into the mechanism of uremic wasting and the response to exercise we examined myostatin expression. Unilateral plantaris muscle WO was initiated in uremic and pairfed (PF) normal rats by ablation of a gastrocnemius tendon and adjoining part of this muscle with the contralateral plantaris as a control. Some rats were GH treated for 7 days. WO led to similar gains in plantaris weight in both groups and corrected the uremic muscle atrophy. GH increased plantaris IGF-1 mRNA >twofold in PF rats but the response in uremia was severely attenuated. WO increased the IGF-1 mRNA levels significantly in both uremic and PF groups, albeit less brisk in uremia; however, after 7 days IGF-1 mRNA levels were elevated similarly, >2-fold, in both groups. In the atrophied uremic plantaris muscle basal myostatin mRNA levels were increased significantly and normalized after an increase in WO suggesting a myostatin role in the wasting process. In the hypertrophied uremic left ventricle the basal myostatin mRNA levels were reduced and likely favor the cardiac hypertrophy. Together the findings provide insight into the mechanisms of skeletal muscle wasting in uremia and the hypertrophic response to exercise, and suggest that alterations in the balance between IGF-1 and myostatin play an important role in these processes.

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To investigate the mechanisms of myofibroblast differentiation of interstitial fibroblastic cells (FCs) in rats with uranyl acetate-induced acute renal failure (ARF), we examined the relationship between the expression of alpha-smooth muscle actin (alpha-SMA), myofibroblast phenotype and tubular dilatation as well as cell shape and adhesion of FCs. Peritubular alpha-SMA-positive myofibroblasts appeared after induction of ARF and extended along the damaged, dilated proximal tubules and then almost disappeared after proximal tubular recovery. The perimeter of proximal tubules correlated with fractional areas stained for alpha-SMA (P<0.001). Most alpha-SMA-positive cells did not incorporate [3H]-thymidine, indicating a low proliferative activity. Transmission electron microscopy showed that FCs increasingly attached to the tubular basement membrane by elongated cytoplasm-containing microfilament bundles, which formed abundant adherens and gap junctions from day 4 to day 7. Scanning electron microscopy showed hypertrophic FCs covering large areas of tubules after induction of ARF. Administration of chlorpromazine, which can inhibit cytoskeletal movement, after induction of ARF partially inhibited myofibroblast differentiation of FCs immunohistochemically and morphologically and resulted in more dilated proximal tubules in concert with aggravation of renal dysfunction and inhibition of regenerative repair at day 4 than vehicle-administered rats. Our results indicate that mechanical tension, judged by tubular dilatation, may contribute to the induction of alpha-SMA phenotype with increased stress fiber formation and intercellular junctions in FCs to support damaged nephron structures by adjusting tensional homeostasis in rats with uranyl acetate-induced ARF.