Search

Upregulation of muscular adiponectin could act as a local protective mechanism to counteract cellular damage in obesity by weakening inflammation, oxidative stress, and apoptosis. To test this hypothesis, adiponectin-knockout (KO) and wild-type (WT) mice were fed a Western diet (WD). WT mice under WD conditions displayed 63% higher adiponectin expression in myocytes than those under standard laboratory diet (SLD) conditions (P = 0.011). WD-fed KO mice exhibited approximately threefold larger myocyte degeneration than WT mice (P = 0.003). Even under SLD conditions, myotubes of KO mice displayed already moderate immunolabeling for markers of oxidative stress (peroxiredoxin-3/5) and for a lipid peroxidation product (hydroxynonenal). Expression of tumor necrosis factor-α (TNF-α) and caspase-6, a marker of apoptosis, was also present. After WD challenge, immunoreactivity for these markers was strong in muscle of KO mice, although it was detected to a lesser extent in WT mice. Activation of NF-κB and caspase-6 doubled in myocytes of WD-fed KO mice when compared to WT mice (P < 0.001). Furthermore, muscle electrotransfer of the adiponectin gene prevented these abnormalities in WD-fed KO mice. Finally, gene abrogation of the adiponectin receptor 1 (AdipoR1) by siRNA recapitulated a pro-inflammatory state in C2C12 myotubes. Thus, upregulation of muscular adiponectin may be triggered by obesity and be crucial locally to counteract oxidative stress, inflammation, and apoptosis. These effects operate in an autocrine/paracrine manner via AdipoR1 and down-regulation of NF-κB signaling.

Adiponectin (ApN) is a hormone tightly linked to the metabolic syndrome where it exerts anti-diabetic actions. It is also known to possess powerful anti-inflammatory effects on skeletal muscle exposed to acute and chronic inflammation. We have previously tested the implication of ApN in Duchenne Muscular Dystrophy (DMD) by generating transgenic mdx mice overexpressing ApN. We showed that ApN can act as preventive agent and delay disease progression. ApN upregulation was capable of reducing muscle inflammation/injury and improving force/myogenesis. Here we took an a contrario approach and crossed mdx mice with ApN knockout mice, in order to obtain mdx with ApN depletion (mdx-KO). The aims were to (1) test whether ApN deficiency could worsen the mdx phenotype and (2) test if ApN supplementation can counteract all abnormalities once the disease has settled. Mdx-KO mice exhibited lower global muscle force/endurance as well as increased muscle damage when compared to regular mdx mice. We next injected and electro-transferred one tibialis anterior with the ApN gene, while the contralateral muscle received and empty plasmid and served as a control. Local administration of the ApN gene significantly reduced the expression of two oxidative stress markers (PRDX3, HNE), two inflammatory markers (TNFα, IL-1β), as well as the number of M1 macrophages. In addition, the expression of an anti-inflammatory cytokine (IL-10) was markedly increased. Local administration of ApN was also able to increase the expression of two major factors of muscle differentiation (Myogenin, Mrf4), one key marker of muscle regeneration (Myh3), plus induce a switch towards a resistant oxidative fiber phenotype. Finally, the presence of ApN markedly reduced NF-κB, a maestro of muscle inflammation and myogenesis. ApN proves to be, yet again, a powerful protector of the skeletal muscle, thus making it a potential therapeutic agent for DMD, and for other diseases where inflammation plays a crucial role. [Award: the Duchenne research fund prize, for the best presentation by a young researcher on the treatment of Duchenne muscular dystrophy]