Adiponectin resistance in skeletal muscle: pathophysiological implications in chronic heart failure

Abstract

Skeletal muscle wasting is a common complication of chronic heart failure (CHF) and linked to poor patient prognosis. In recent years, adiponectin was postulated to be centrally involved in CHF-associated metabolic failure and muscle wasting. This review discusses current knowledge on the role of adiponectin in CHF. Particular emphasis will be given to the complex interaction mechanisms and the intracellular pathways underlying adiponectin resistance in skeletal muscle of CHF patients. In this review, we propose that the resistance process is multifactorial, integrating abnormalities emanating from insulin signalling, mitochondrial biogenesis, and ceramide metabolism.

Keywords: Adiponectin resistance; Chronic heart failure; Skeletal muscle; Wasting.

Figure 1

Two faces of adiponectin in chronic heart failure. Adiponectin is a beneficial adipokine that is present at high levels in lean, healthy individuals. Low levels of adiponectin have been associated with conditions such as obesitas, hypertension, myocardial infarction, coronary artery disease, and cardiac hypertrophy. In heart failure with reduced ejection fraction, however, increases in circulating adiponectin parallel worsening of prognosis for patients. Based on clinical and experimental evidence, we hypothesize that the adipokine has two faces in heart failure with reduced ejection fraction. Elevated adiponectin likely serves as a protective and compensatory mechanism for the energy metabolic alterations that occur during the early stages of heart failure with reduced ejection fraction. In contrast, in patients with end‐stage heart failure with reduced ejection fraction, high levels of adiponectin will further deteriorate cardiac function, increasing the risk of death. Green, yellow, and red colours indicate normal, low, and high levels of adiponectin, respectively. Arrows point to disease condition.

Figure 2

Adiponectin and chronic heart failure‐associated myopathy. Skeletal muscle hyperadiponectinemia contributes to energetic impairments, structural, and functional alterations of muscle fibres and hormonal imbalances, eventually culminating into a state of chronic heart failure‐associated myopathy.

Figure 3

Hypothesis on skeletal muscle adiponectin resistance in chronic heart failure. In chronic heart failure, insulin resistance is associated with decreased levels of phosphatidylinositol 3‐kinase/Akt/forkhead box protein O1 and a reduced expression of the adiponectin receptor AdipoR1. Skeletal muscle metabolic deficiency in chronic heart failure is corroborated by a deactivated adenosine monophosphate activated protein kinase/sirtuin 1/peroxisome proliferator‐activated receptor α pathway and down‐regulation of peroxisome proliferator‐activated receptor ƴ coactivator1 α, ultimately progressing to a state of skeletal muscle adiponectin resistance. This adiponectin resistance contributes to lipotoxicity, and further worsens insulin resistance. All these facets infer a disease process that eventually fulminates into skeletal muscle wasting.