Abstract
Abundant evidence reveals that activation of the renin-angiotensin system promotes skeletal muscle atrophy in several conditions including congestive heart failure, chronic kidney disease, and prolonged mechanical ventilation. However, controversy exists about whether circulating angiotensin II (AngII) promotes skeletal muscle atrophy by direct or indirect effects; the centerpiece of this debate is the issue of whether skeletal muscle fibers express AngII type 1 receptors (AT1Rs). While some investigators assert that skeletal muscle expresses AT1Rs, others argue that skeletal muscle fibers do not contain AT1Rs. These discordant findings in the literature are likely the result of study design flaws and additional research using a rigorous experimental approach is required to resolve this issue. We tested the hypothesis that AT1Rs are expressed in both human and rat skeletal muscle fibers. Our premise was tested using a rigorous, multi-technique experimental design. First, we established both the location and abundance of AT1Rs on human and rat skeletal muscle fibers by means of an AngII ligand-binding assay. Second, using a new and highly selective AT1R antibody, we carried out Western blotting and determined the abundance of AT1R protein within isolated single muscle fibers from humans and rats. Finally, we confirmed the presence of AT1R mRNA in isolated single muscle fibers from rats. Our results support the hypothesis that AT1Rs are present in both human and rat skeletal muscle fibers. Moreover, our experiments provide the first evidence that AT1Rs are more abundant in fast, type II muscle fibers as compared with slow, type I fibers. Together, these discoveries provide the foundation for an improved understanding of the mechanism(s) responsible for AngII-induced skeletal muscle atrophy.
Highlights
The renin-angiotensin system (RAS) is well known for its role in the regulation of blood pressure, fluid homeostasis, and electrolyte balance
AngII type 1 receptors (AT1Rs) Abundance in Rat Skeletal Muscles Determined by angiotensin II (AngII)-Binding Assay
Our results reveal that AT1Rs exist in the diaphragm, soleus, and plantaris muscles, as evidenced by a well-defined fluorescence label along the sarcolemma of muscle fibers which agrees with the known location of AT1Rs (Figure 1A (a–c))
Summary
The renin-angiotensin system (RAS) is well known for its role in the regulation of blood pressure, fluid homeostasis, and electrolyte balance. RAS signaling promotes skeletal muscle atrophy (reviewed in [1,2,3,4]). Congestive heart failure, chronic kidney disease, and prolonged bed rest are all conditions associated with skeletal muscle atrophy resulting from elevated circulating angiotensin II (AngII) [5,6,7,8,9]. Elevated plasma levels of cortisol, IL-6, or SAA can independently, or collectively, stimulate skeletal muscle atrophy [10]. Elevated cortisol promotes muscle atrophy by increasing proteolysis and decreasing muscle protein synthesis [11]. High concentrations of IL-6 and SAA act synergistically to evoke muscle atrophy by depressing Akt/mTOR signaling resulting in decreased muscle protein synthesis and accelerated proteolysis [10]
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