Angiotensin II, oxidative stress and skeletal muscle wasting

Abstract

Muscle atrophy (cachexia) is a muscle wasting syndrome associated with several pathological conditions in humans such as congestive heart failure, diabetes, AIDS, cancer and renal failure, and the presence of cachexia worsens outcome. Many of the conditions associated with cachexia are accompanied by stimulation of the renin-angiotensin system and elevation in angiotensin II (ang II) levels. Ang II infusion induces skeletal muscle atrophy in rodents and mechanisms include increased expression of the E3 ligases atrogin-1/MuRF-1, an elevated rate of ubiquitin-proteasome mediated proteolysis and increased reactive oxygen species (ROS) levels, closely mimicking conditions of human cachexia. Ang II-induced oxidative stress contributes to muscle atrophy in a mouse model. Nicotinamide adenine dinucleotide phosphate oxidase- and mitochondria-derived ROS contribute to ang II-induced oxidative stress. Specific targeting of ROS and nicotinamide adenine dinucleotide phosphate oxidase/mitochondria cross-talk could be a beneficial, novel therapy to treat cachexia.

FIGURE 1

Hypothetic mechanism of Angiotensin II (ang II)-induced muscle wasting involving oxidative stress. Ang II increases both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase- and mitochondrial-derived reactive oxygen species (ROS) in skeletal muscle and reduces appetite through central effects. NADPH oxidase/mitochondria crosstalk mechanism amplifies ROS and activates proteasome system-mediated muscle protein degradation. Loss of appetite and proteasome activation contributes to ang II-induced skeletal muscle atrophy. Dashed lines depict hypothetical pathways.