Pathophysiological implications of adiponectin upregulation in skeletal muscle during inflammatory and metabolic stress
(2012)
Files
Fichierpdf1ermai.pdf
Restricted Access - Adobe PDF
- 4.4 MB
Details
- Authors
- Supervisors
- Brichard, Sonia
- Abstract
- (en) Skeletal muscle has been recognized as an “endocrine” organ that secretes cytokines/hormones collectively referred to as myokines. These myokines exert their effects mainly in an autocrine/paracrine manner and less frequently via an “endocrine” mode. Emerging studies point out the presence of ApN in non-adipose tissues, such as skeletal muscle where ApN has been detected within the myofibers. We have previously shown that ApN may be induced in mouse skeletal muscle following an acute inflammation (like that caused by LPS injection) or a metabolic/oxidative stress (like that occurring in obese and insulin-resistant ob/ob mice). We hypothesized that this induction of muscular ApN could be viewed as a local protective mechanism to counteract deleterious inflammatory reactions and oxidative damage. We therefore investigated the effects of ApN in muscle in two different situations: after an inflammatory challenge and following a metabolic challenge. Firstly, we examined whether muscles of ApN-knockout (ApN-KO) mice exhibited higher degree of oxidative stress and apoptosis than those of wild-type (WT) mice when challenged by LPS and whether these abnormalities may be corrected by local administration of ApN. We found that muscles of ApN-KO mice exhibited myocyte degenerescence when compared to WT mice, especially after LPS injection. We searched for the underlying mechanisms. Even in the basal state, myocytes of ApN-KO displayed a positive immunolabelling for 3 markers of oxidative stress (peroxiredoxin (PRDX) 3/5 and heme oxygenase-1 (HO-1)) as well as for a lipid peroxidation product (hydroxynonenal (HNE)). The pro-inflammatory cytokine (TNF-α) and a marker of apoptosis (caspase-6) were also already present in the basal condition in muscle of these ApN-KO mice, but not in those of WT mice. After LPS injection, immunoreactivity for these markers was much stronger in muscle of ApN-KO mice, while being only slightly detected in WT mice. Eventually, transfer of ApN gene prevented muscle stress in ApN-KO mice challenged by LPS. We showed then an activation of nuclear factor (NF-κB) in ApN-KO muscle. This activation was reduced by muscular transfection of ApN. These results have been confirmed in vitro. Secondly, we hypothesized that the upregulation of muscular ApN in obese mice could be viewed as a local protective mechanism to counteract the metabolic stress. To test this hypothesis, ApN-KO mice and WT mice were rendered obese and insulin-resistant by administration of a western diet (WD; high-fat/high sucrose). We first extended our data in ob/ob mice and showed that WT mice rendered obese by the WD diet, unlike those receiving the standard diet (SD), displayed a positive labelling for ApN in myocytes. When challenged by the WD, ApN-KO mice were more obese and insulin-resistant than WT mice. ApN-KO after WD exhibited ~3-fold larger myocyte degenerescence when compared to WT mice. After the WD challenge, immunoreactivity for markers of oxidative stress (PRDX3/5, HNE), of inflammation (TNF-α) and apoptosis (caspase-6) as mentioned above was much stronger in muscle of ApN-KO mice compared to WT mice. The percentage of NF-κB immunolabelled nuclei also increased in both type of mice under WD diet but remained larger in ApN-KO. As described for LPS study, transfer of ApN gene prevented muscle stress in ApN-KO mice challenged by the WD (reduction of oxidative stress and inflammatory markers compared to the contro-lateral untreated muscle). We then showed that AdipoR1-specific abrogation induced an increased inflammation in C2C12 cells. Thus, the presence of ApN acts in an auto/paracrine manner to maintain the inflammatory/immune balance of myocyte via AdipoR1 and subsequent downregulation of NF-κB signaling. ApN upregulation could exert beneficial effects in diseases where chronic inflammation and oxidative stress play determinant roles.
- Affiliations
Citations
Jortay, J. (2012). Pathophysiological implications of adiponectin upregulation in skeletal muscle during inflammatory and metabolic stress. https://hdl.handle.net/2078.5/76484