Insulin-like growth factor-1 restores dexamethasone-induced heart growth arrest in rats: the role of the ubiquitin pathway

Abstract

ObjEctIvE: In skeletal muscle, glucocorticoids induce catabolism and proteolysis which is accomplished via the ubiquitin (Ub) proteolytic pathway. cardiac muscle is a striated muscle which, compared to skeletal muscle, more abundantly expresses components of the Ub pathway, thus suggesting an important role for this pathway in heart physiology. the aim of our study was to explore the role of the Ub pathway in heart muscle physiology. DEsIGN: We treated rats for three days with a pharmacologic dose of dexamethasone (DEXA) 0.5mg/100g body weight (bW). An attempt was also made to counteract the DEXA effect by co-treatment with insulinlike growth factor-1 (IGF-1; 0.35mg/100g bW). rEsULts: DEXA treatment caused a 7.8% decrease in heart weight compared to control (p<0.05) and also increased heart tissue levels of the ubiquitin-conjugating enzyme E2 and the 20s proteasome protein. Myofibrillar proteins degraded by the ubiquitin pathway (α-actin, myoglobin, and troponin 1) were all decreased by DEXA, while ubiquitinated forms of α-actin were increased. Co-treatment with IGF-1 completely prevented DEXA-induced decrease in heart weight, an effect which was accompanied by decreased heart tissue levels of several ubiquitinated proteins including α-actin, the 20S proteasome protein, E2-14kDa mrNA, and c-3 proteasome subunit mrNA, while the levels of non-ubiquinated α-actin, myoglobin, and troponin 1 were all partially restored. CONCLUSION: these results demonstrate that DEXA activates the ubiquitin proteolytic pathway in the heart and that IGF-1 efficiently counteracts this effect. Our findings reveal a possible mechanism for the anti-proteolytic actions of IGF-1 and its cardioprotective role involving the Ub pathway.

Paracrine Effects of IGF-1 Overexpression on the Functional Decline Due to Skeletal Muscle Disuse: Molecular and Functional Evaluation in Hindlimb Unloaded MLC/mIgf-1 Transgenic Mice

“…Despite the plentiful literature showing the clear role of IGF-1 in muscle hypertrophy and regeneration [17], [64], [65], we found that IGF-1 does not protect all the parameters altered by muscle disuse in the HU model. Various hypotheses can be formulated to explain this apparent discrepancy.…”

Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function

“…We found that IGF-1 mildly increased the size of hPSC-CMs, but more importantly proved an essential factor in revealing a positive functional role for the glucocorticoid dexamethasone in this system. Synergistic effects for IGF-1 and dexamethasone have been reported in skeletal muscle and heart, with pro-differentiation and anti-atrophic effects observed ( Chrysis et al., 2011 , Pansters et al., 2013 , Schakman et al., 2008 ). Glucocorticoids also promote the structural and functional maturation of fetal mouse cardiomyocytes ( Rog-Zielinska et al., 2013 , Rog-Zielinska et al., 2015 ) but have little effect on hPSC-CMs when added alone although do affect calcium handling (G.K., C.L.M., M. Bellin, B. van Meer, L. Tertoolen, and S. Casini, unpublished data).…”

Thyroid hormone upregulates MDM2 in rat type I fibre: Implications for skeletal muscle mass regulation

“…Previous observations have shown that high levels of T3 stimulate the ubiquitin‐proteasome–dependent protein breakdown in skeletal muscle, which is considered to be the main pathway of proteolysis of myofibrillar proteins in skeletal muscle . In this system, E3 ligases ubiquitinate target proteins that will be directed and degraded at the 26S proteasome.…”