Local Induction of Adiponectin Reduces Lipopolysaccharide-Triggered Skeletal Muscle Damage

Adiponectin (ApN) exhibits metabolic and antiinflammatory properties. This hormone is exclusively secreted by adipocytes under normal conditions. We have shown that ApN was induced in tibialis anterior muscle of mice injected with lipopolysaccharide (LPS) and in C2C12 myotubes cultured with proinflammatory cytokines. We hypothesized that muscle ApN could be a local protective mechanism to counteract excessive inflammatory reaction and oxidative damage. To test this paradigm, we examined whether muscles of ApN-knockout (KO) mice exhibit a higher degree of oxidative stress and apoptosis than wild-type mice when challenged by ip LPS and whether these abnormalities may be corrected by local administration of ApN. Eventually we investigated the effects of ApN in vitro. When compared with wild-type mice, ApN-KO mice exhibited myocyte degenerescence, especially after LPS. Myocytes of ApN-KO mice also displayed much stronger immunolabeling for markers of oxidative stress (peroxiredoxin-3/5 and heme oxygenase-1) as well as for a lipid peroxidation product (hydroxynonenal). Expression of TNF-alpha, caspase-6, a marker of apoptosis, and nuclear factor-kappa B was enhanced as well. Eventually muscle electrotransfer of the ApN gene, which did not induce any rise of systemic ApN, corrected all these abnormalities in LPS-injected ApN-KO mice. Likewise, ApN attenuated LPS-induced production of proinflammatory cytokines and activation of nuclear factor-kappa B in C2C12 cells. Thus, induction of ApN into skeletal muscle in response to an inflammatory aggression appears to be a crucial mechanism to counteract in an autocrine or paracrine fashion excessive inflammatory damage, oxidative stress, and subsequent apoptosis. (Endocrinology 151: 4840-4851, 2010)