Skeletal muscle deiodinase type 2 regulation during illness in mice

Abstract

We have previously shown that skeletal muscle deiodinase type 2 (D2) mRNA (listed as Dio2 in MGI Database) is upregulated in an animal model of acute illness. However, human studies on the expression of muscle D2 during illness report conflicting data. Therefore, we evaluated the expression of skeletal muscle D2 and D2-regulating factors in two mouse models of illness that differ in timing and severity of illness: 1) turpentine-induced inflammation, and 2) Streptococcus pneumoniae infection. During turpentineinduced inflammation, D2 mRNA and activity increased compared to pair-fed controls, most prominently at day 1 and 2, whereas after S. pneumoniae infection D2 mRNA decreased. We evaluated the association of D2 expression with serum thyroid hormones, (de-)ubiquitinating enzymes ubiquitin-specific peptidase 33 and WD repeat and SOCS box-containing 1 (Wsb1), cytokine expression and activation of inflammatory pathways and cAMP pathway.During chronic inflammation the increased muscle D2 expression is associated with the activation of the cAMP pathway. The normalization of D2 5 days after turpentine injection coincides with increased Wsb1 and tumor necrosis factor a expression. Muscle interleukin-1b (Il1b) expression correlated with decreased D2 mRNA expression after S. pneumoniae infection. In conclusion, muscle D2 expression is differentially regulated during illness, probably related to differences in the inflammatory response and type of pathology. D2 mRNA and activity increases in skeletal muscle during the acute phase of chronic inflammation compared to pair-fed controls probably due to activation of the cAMP pathway. In contrast, muscle D2 mRNA decreases 48 h after a severe bacterial infection, which is associated with local Il1b mRNA expression and might also be due to diminished food-intake.

The molecular basis of the non-thyroidal illness syndrome

“…While acute inflammation decreases muscle D3 (Kwakkel et al 2010), bacterial sepsis does not affect D3 and chronic inflammation even increases D3 expression (Kwakkel et al 2009). In critically ill patients, muscle D3 is also increased (Peeters et al 2003).…”

“…In critically ill patients, muscle D3 is also increased (Peeters et al 2003). These changes seem to be independent on inflammatory pathways since neither sepsis nor chronic inflammation induces phosphorylation of the NF-kB and ERK pathways (Kwakkel et al 2009). In proliferating myoblasts, D3 functions as a survival factor by decreasing TH concentrations and suppressing TH induced FoxO3 mediated gene expression (Dentice et al 2014).…”

“…Dio2 expression in skeletal muscle increases in intensive-care unit patients (Mebis et al 2007), in several NTIS animal models of acute (Kwakkel et al 2008) and chronic inflammation (Kwakkel et al 2009), while in septic patients and mice muscle Dio2 expression decreases (Rodriguez-Perez et al 2008, Kwakkel et al 2009). The increased Dio2 expression during chronic inflammation is likely due to enhanced CREB signalling (Kwakkel et al 2009), while the decrease during sepsis might be mediated by decreased food intake since 62 h of fasting decreased muscle Dio2 expression in healthy volunteers (Heemstra et al 2009) (see Fig. 3).…”

“…In line with these findings, there is no evidence that ubiquitination is involved in the regulation of D2 during inflammation. Also in muscle, where D2 expression and activity is increased upon inflammation, WSB-1 and USP-33 expression is not correlated with the increased D2 activity during chronic inflammation and sepsis (Kwakkel et al 2009). …”

Is there a link between polycystic ovary syndrome and non-thyroidal illness syndrome?

“…It was suggested that, together, these modifications in deiodinase expression could be a major factor involved in causing the low T3 concentration that is associated with NTIS. The trigger for these changes in deiodinase expression has been attributed to an increase in proinflammatory cytokines, which often occurs in NTIS (35)(36)(37)(38)(39).…”