Functional Adiponectin Resistance at the Level of the Skeletal Muscle in Mild to Moderate Chronic Heart Failure

Abstract

Background— Adiponectin is an antiinflammatory, insulin-sensitizing, and antiatherogenic adipocytokine that plays a fundamental role in energy homeostasis. In patients with chronic heart failure (CHF), high circulating adiponectin levels are associated with inverse outcome. Recently, adiponectin expression has been identified in human skeletal muscle fibers. We investigated the expression of adiponectin, the adiponectin receptors, and genes involved in the downstream lipid and glucose metabolism in the skeletal muscle of patients with CHF. Methods and Results— Muscle biopsies (vastus lateralis muscle) were obtained from 13 patients with CHF and 10 healthy subjects. mRNA transcript levels of adiponectin, adiponectin receptors (AdipoR1 and AdipoR2), and downstream adiponectin-related enzymes were quantified by real-time reverse transcriptase polymerase chain reaction. Adiponectin expression in the skeletal muscle of patients with CHF was 5-fold higher than in healthy subjects ( P <0.001), whereas AdipoR1 was downregulated ( P =0.005). In addition, the expression of the main genes involved in downstream pathway (peroxisome proliferator-activated receptor-α [PPAR-α] and both AMP-activated protein kinase-α1 and -α2 subunits) as well as their target genes in lipid (acyl-coenzyme A dehydrogenase C-14 to C-12 straight chain) and glucose metabolism (hexokinase-2) were significantly reduced in CHF. The strong positive correlation found between AdipoR1 and PPAR-α/AMP-activated protein kinase gene expression was confirmed in PPAR-α null mice, suggesting a cause-and-effect relationship. Immunohistochemical staining confirmed the presence of adiponectin in the skeletal muscle. Conclusions— Despite increased adiponectin expression in the skeletal muscle, patients with CHF are characterized by downregulation of AdipoR1 that is most probably linked to deactivation of the PPAR-α/AMP-activated protein kinase pathway. These facts suggest functional adiponectin resistance at the level of the skeletal muscle in CHF.