Intramuscular renin–angiotensin system is activated in human muscular dystrophy

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase

“…For a better quantification, the same genes were measured in parallel in dystrophic mdx EDL muscle, based on our recent confirmation of a higher expression of NOX-2 and tubulin ␣-1b in gastrocnemius muscle of this genotype (12, 59, 74). The AT 1 a/b receptor, angiotensinogen, and ACE were expressed in EDL muscle and, surprisingly (70), at comparable level in WT and mdx mice (Fig. 3); as expected NOX2 (gp91phox) and tubulin ␣-1b were markedly overexpressed in mdx vs. WT animals.…”

“…RAS and ANG II might be involved in skeletal muscle wasting and regeneration impairment, via ROS production, activation of ubiquitinmediated protein degradation, and interference with metabolism and insulin-like growth factor I signaling (41,43,50,63,73). Accordingly, a role of RAS in heart and skeletal muscle damage in muscular dystrophy has been proposed (13,14,70). Many of the above actions have been observed upon in vivo manipulation of the RAS system or in cell lines, and little few evidence is available about direct actions of ANG II on adult myofibers (43,45,69,78).…”

“…ANG II is known for its actions in cardiovascular system and its involvement in heart disease; however, it has been claimed that ANG II exerts prooxidant, proinflammatory, and profibrotic action in several tissues, among which is skeletal muscle (13,69,73). Increasing evidence supports a key role of enhanced activation of systemic and local renin-angiotensin system (RAS) and ANG II in aberrant remodeling and wasting conditions of skeletal muscle, including muscular dystrophy (13,41,43,70). Other than in microvasculature, the presence of ANG II receptors type 1 (AT 1 ) and 2 (AT 2 ) in myofibers and muscle cell lines has been described, although controversy is still unresolved about the role of these tissue receptors in mediating the ANG II actions in mature skeletal muscle (41,43,45,69,78).…”

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

“…This study highlighted that a neutralising antibody to TGFwould be expected to antagonize all sources of active TGF-, including those activated during muscle degeneration through the release of fibrillin-1 [384] and those not in the proximity of AT1 receptors, and thus may be more efficacious than AT1 antagonists in degenerative diseases. Recent studies have confirmed the presence of a local RAS in SM and associated muscle stem cells in both mdx [385] and DMD muscle [386], and have unveiled a role for ATII in the regulation of muscle satellite cell activation and chemotaxis, particularly in the immediate aftermath of muscle injury [387]. ATII may also exert TGF--independent effects that could contribute to muscle degeneration, impaired regeneration and fibrosis.…”

Response to Letter Regarding Article, “Early Treatment With Lisinopril and Spironolactone Preserves Cardiac and Skeletal Muscle in Duchenne Muscular Dystrophy Mice”

“…However, one study of muscle biopsies from patients with Duchenne muscular dystrophy shows upregulation of angiotensin-converting enzyme in dystrophic in comparison with normal muscle. 2 Because of the relatively mild fibrosis in mdx mice, we used utrn Ϯ ;mdx in our study, which develop much more fibrosis than the mdx model 3 used by Bauer et al 4 Given the quantitative difference in fibrosis in these different models, we should not conclude that spironolactone by itself is responsible for the antifibrotic action, and must retain the possibility that the observed effects could result from additive or synergistic action of these drugs. 1 Bauer and colleagues' other work 5 showing that spironolactone is protective against steroid-induced cardiac dysfunction but not fibrosis raises important questions as to what aspect of the combination treatment specifically attenuated cardiac fibrosis in our drug combination study.…”