ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

Abstract

Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin–angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.

The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis?

“…RAS components are expressed in satellite cells and contribute to muscle regeneration and age-associated muscle changes [ 38 ]. Importantly, abundant evidence suggested that the protective axis of tRAS protects from pathological muscle remodeling and muscle insulin resistance [ 39 ]. The workgroup of Delafontaine et al sowed that AngII was working through NADPH and mitochondria-derived ROS generation [ 40 ].…”

Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk

“…The deleterious crosstalk between RAGE and RAS might be active also in the muscles of severe COVID-19 patients who develop cachexia [108], a complex metabolic syndrome characterized by the loss of muscle mass and body weight, since both RAGE and RAS signals play crucial roles in inducing muscle protein breakdown [109]. Skeletal muscle tissue expresses a considerable amount of ACE2 [110], making muscles potential targets of SARS-CoV-2. Deletion of ACE2 in mice translated into early manifestations of muscle weakness with signatures of muscle senescence [111], suggesting that the SARS-CoV-2dependent downregulation of ACE2 might predispose COVID-19 patients to cachexia.…”

Developing new drugs that activate the protective arm of the renin–angiotensin system as a potential treatment for respiratory failure in COVID-19 patients

“…Indeed, mechanical ventilation, the main supportive therapy for ARDS patients, induces ventilator-induced diaphragmatic dysfunction (VIDD) [44] , which is characterized by a contractile dysfunction and a rapid muscular atrophy [45] . Muscular disorders may result from a RAS imbalance [46] . It has been shown that Ang-II induces diaphragm muscle wasting and respiratory muscle dysfunction [47] , whereas Ang-(1–7) exerts a protective action in a rat model of VIDD [48] and could improve muscular functions in patients infected by SARS-CoV-2 [46] .…”

“…Muscular disorders may result from a RAS imbalance [46] . It has been shown that Ang-II induces diaphragm muscle wasting and respiratory muscle dysfunction [47] , whereas Ang-(1–7) exerts a protective action in a rat model of VIDD [48] and could improve muscular functions in patients infected by SARS-CoV-2 [46] .…”