Mas Receptor Activation Slows Tumor Growth and Attenuates Muscle Wasting in Cancer

Murphy, Kate T.; Hossain, Mohammed Iqbal; Swiderski, Kristy; Chee, Annabel; Naim, Timur; Trieu, Jennifer; Haynes, Vanessa; Read, Suzannah J.; Stapleton, David; Judge, Sarah M.; Treviño, José G.; Judge, Andrew R.; Lynch, Gordon S.

doi:10.1158/0008-5472.can-18-1207

Cited by 34 publications

(32 citation statements)

References 40 publications

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“…To provide a second approach to the question of whether AT1Rs are expressed in skeletal muscle, we utilized a recently validated AT1R antibody and performed Western blots on protein homogenates from isolated single muscle fibers [ 25 ]. These results corroborate the presence of AT1Rs in skeletal muscle fibers and provide additional support for the hypothesis that skeletal muscles express AT1Rs.…”

Section: Resultsmentioning

confidence: 99%

“…The muscle fiber homogenates were, then, boiled for 5 min. Proteins within the homogenate were separated via polyacrylamide gel electrophoresis, transferred onto a PVDF membrane, and incubated with an AT1R antibody that had recently been validated with both knockout and overexpression animals [ 25 ]. The AT1R antibody was a gift of Dr. Kate Murphy (University of Melbourne, Melbourne, Australia).…”

Section: Methodsmentioning

confidence: 99%

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Human and Rodent Skeletal Muscles Express Angiotensin II Type 1 Receptors

Deminice

Hyatt

Yoshihara

et al. 2020

Cells

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Human and Rodent Skeletal Muscles Express Angiotensin II Type 1 Receptors

Deminice

Hyatt

Yoshihara

et al. 2020

Cells

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“…With this limitation in mind, several proteins of interest were identified as potential AT1R independent mediators of Ang-(1-7)/Mas1 signaling (S2 Table). Mas1 was first described as an oncogene [64] and continues to be of interest in cancer [65,66]. Therefore, PAX4 and PA2G4, both of which are implicated in the development of cancer [35,38,39] and were identified here as a potential mediators of AT1R independent Ang-(1-7)/Mas1 signaling, represent ideal candidates for further study.…”

Section: Plos Onementioning

confidence: 89%

Interaction between Mas1 and AT1RA contributes to enhancement of skeletal muscle angiogenesis by angiotensin-(1-7) in Dahl salt-sensitive rats

et al. 2020

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The heptapeptide angiotensin-(1-7) (Ang-(1-7)) is protective in the cardiovascular system through its induction of vasodilator production and angiogenesis. Despite acting antagonistically to the effects of elevated, pathophysiological levels of angiotensin II (AngII), recent evidence has identified convergent and beneficial effects of low levels of both Ang-(1-7) and AngII. Previous work identified the AngII receptor type I (AT1R) as a component of the protein complex formed when Ang-(1-7) binds its receptor, Mas1. Importantly, pharmacological blockade of AT1R did not alter the effects of Ang-(1-7). Here, we use a novel mutation of AT1R A in the Dahl salt-sensitive (SS) rat to test the hypothesis that interaction between Mas1 and AT1R contributes to proangiogenic Ang-(1-7) signaling. In a model of hind limb angiogenesis induced by electrical stimulation, we find that the restoration of skeletal muscle angiogenesis in SS rats by Ang-(1-7) infusion is impaired in AT1R A knockout rats. Enhancement of endothelial cell (EC) tube formation capacity by Ang-(1-7) is similarly blunted in AT1R A mutant ECs. Transcriptional changes elicited by Ang-(1-7) in SS rat ECs are altered in AT1R A mutant ECs, and tandem mass spectrometry-based proteomics demonstrate that the protein complex formed upon binding of Ang-(1-7) to Mas1 is altered in AT1R A mutant ECs. Together, these data support the hypothesis that interaction between AT1R and Mas1 contributes to proangiogenic Ang-(1-7) signaling.

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“…A recent study has implicated activation of the Mas receptor (see Sect. 2.3.7 above) in the attenuation of muscle wasting in cachexia (Murphy et al 2018).…”

Section: Cachexiamentioning

confidence: 93%