Abstract
Patients with advanced congestive heart failure (CHF) or chronic kidney disease often have increased angiotensin II (Ang II) levels and cachexia. We previously demonstrated that Ang II, via its type 1 receptor, causes muscle protein breakdown and apoptosis and inhibits satellite cell (SC) proliferation and muscle regeneration, likely contributing to cachexia in CHF and chronic kidney disease. In contrast, Ang II, via its type 2 receptor (AT2R) expression, is robustly induced during SC differentiation, and it potentiates muscle regeneration. To understand the mechanisms regulating AT2R expression and its potential role in muscle regeneration in chronic diseases, we used a mouse model of CHF and found that muscle regeneration was markedly reduced and that this was accompanied by blunted increase of AT2R expression. We performed AT2R promoter reporter analysis during satellite cell differentiation and found that the 70 bp upstream of the AT2R transcription start site contain a core promoter region, and regions upstream of 70 bp to 3 kbp are dispensable for AT2R induction. Instead, AT2R intron 2 acts as a transcriptional enhancer during SC differentiation. Further deletion/mutation analysis revealed that multiple transcription factor binding sites in the +286/+690 region within intron 2 coordinately regulate AT2R transcription. Importantly, +286/+690 enhancer activity was suppressed in CHF mouse skeletal muscle, suggesting that AT2R expression is suppressed in CHF via inhibition of AT2R intronic enhancer activity, leading to lowered muscle regeneration. Thus targeting intron 2 enhancer element could lead to the development of a novel intervention to increase AT2R expression in SCs and potentiate skeletal muscle regenerative capacity in chronic diseases.
Highlights
Overactivation of the renin-angiotensin system (RAS)2 contributes to the pathophysiology of many chronic disease conditions
Skeletal Muscle Regeneration and Induction of AT2R Expression Are Reduced in congestive heart failure (CHF)—We have shown that the RAS plays an important role in causing skeletal muscle wasting in CHF and possibly other chronic disease conditions (3– 8, 39 – 41)
Our recent findings indicate that different subtypes of angiotensin II (Ang II) receptors AT1R and AT2R regulate different stages of satellite cell (SC) differentiation and skeletal muscle regeneration, potentially contributing to the development of muscle wasting in CHF [9, 37, 38]
Summary
Overactivation of the renin-angiotensin system (RAS) contributes to the pathophysiology of many chronic disease conditions. Cachexia is typically associated with skeletal muscle atrophy, and increasing evidence has suggested that elevated levels of Ang II lead to muscle atrophy in chronic disease conditions [3,4,5,6,7,8,9]. LAD+CTX regeneration in vivo [38] These data strongly suggest that Ang II regulates different stages of the SC differentiation process via AT1R and AT2R and that balancing AT1R and AT2R signaling is critical to maintain muscle regenerative capacity mediated by SC function. In this study we aimed to identify mechanisms whereby AT2R expression is increased during SC differentiation
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