Activation of the ubiquitin pathway in rat skeletal muscle by catabolic doses of glucocorticoids

Abstract

To evaluate whether catabolic levels of glucocorticoids activate the ubiquitin pathway in conjunction with their known proteolytic effect in skeletal muscle, rats were injected daily with corticosterone (CTC; 10 mg/100 g body wt) for 7 days. Two peaks of urinary excretion of 3-methylhistidine (3-MH), a specific marker of myofibrillar proteolysis, were observed at days 1 and 3 (165 and 295% of controls, respectively). Levels of ubiquitin pathway mRNAs in skeletal muscle were assessed around the 3-MH peaks. In the extensor digitorum longus, a first rise of two polyubiquitin (pUb) mRNAs was seen at day 1 (183 and 162% of control for the UbB and UbC transcripts, respectively, P < 0.01). An accumulation of both E2-14k mRNAs (140%, P < 0.02, and 157% of controls, P < 0.01) and proteasome C8 subunit mRNA (222% of control, P < 0.05) was seen at day 2. A second more important peak of induction of pUb mRNA was seen at day 3 (251 and 217% of controls for the UbB and UbC transcripts, respectively, P < 0.001). All transcripts returned to near control levels by day 4. In the soleus, induction of E2-14k mRNA started at day 3 and reached 216 and 208% of controls at day 4 (P < 0.001), whereas an increase of pUb mRNA was observed at days 3 (213 and 241%, P < 0.05) and 4 (211 and 221%, P < 0.001). A rise of proteasome C8 subunit mRNA accumulation was also seen in the soleus at days 3 (217%, P < 0.05) and 4 (157%, P < 0.05). Reduced ubiquitin conjugate levels, possibly due to their rapid degradation through increased proteasome activity, were observed in both muscle types at day 3. The parallel between the catabolic effects of CTC and activation of the ubiquitin pathway in muscles of CTC-treated rats strongly suggests the involvement of this system in glucocorticoid-induced muscular atrophy.

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

“…This is in contrast with previous literature showing increases of several components of the ubiquitin proteasome system after corticosteroids treatment in in vitro [6,38] and in animal studies [22,39]. To our knowledge, only one in vitro study has demonstrated that treatment of cells (i.e., thymocytes) with dexamethasone decreased proteasome chymotrypsin-like activity in cell extracts [40].…”

“…In vivo administration of corticosteroids to animals has been shown to stimulate the different proteolytic systems [22-26]. On the other hand, there are also evidences suggesting that corticosteroids may provide beneficial effects on skeletal muscles.…”

Effect of insulin on dexamethasone-induced ultrastructural changes in skeletal and cardiac muscle

“…Glucocorticoids induced muscle atrophy by promoting the catabolism and inhibiting anabolism. The involved part molecular and cellular mechanisms have been investigated in succession in mammals (Auclair et al 1997;Hasselgren 1999;Shah et al 2000a, b;Penner et al 2002;Komamura et al 2003;Ma et al 2003;Liu et al 2004;Gilson et al 2007;Schakman et al 2008a). Compared to mammals, the researches for the functional mechanisms of glucocorticoids in avians are fewer.…”

Ubiquitin-proteasome-dependent proteolysis in skeletal muscle

“…Gonen et al [16] [40,41]. In contrast, a decrease in ubiquitin-conjugates was observed during corticosterone treatment [4]. The reasons for such discrepancies are unclear, although it is conceivable that in some cases the changes in the levels of ubiquitin-conjugates may result from alteration in their rates of degradation.…”

“…The precise mechanisms which result in increased ubiquitin expression have not been elucidated. However, there is increased production of glucocorticoids in several catabolic states [35,42,47], and glucocorticoid responsive elements have been detected in the promotors of the chicken and human polyubiquitin genes [4]. Ubiquitin expression is also regulated by insulin [22], and presumably indirectly by several cytokines including tumor necrosis factor-a (TNF-a) [24].…”