The role of the renin-angiotensin signalling pathway in muscle mass preservation during a severe energy deficit in humans

Abstract

Angiotensin I is converted to Angiotensin II (ANGII) by the angiotensin-converting enzymes ACE1 and ACE2. ANGII upregulates the MAPK and ERK1/2 signalling pathways through the angiotensin type I receptor (AT1R). This activates NADPH oxidase and promotes production of ROS, eliciting skeletal muscle (SM) catabolism. Here we study the regulation of SM renin‐angiotensin system (RAS) signalling during a severe energy deficit. We hypothesized that exercise may counteract RAS activation in SM during energy deficit, thereby sparing SM mass. METHODS: Fifteen overweight men underwent 4 days of caloric restriction (CR) (0.8 g/kg BW/day of either whey n=8 or sucrose n=7) and prolonged exercise (PE) (45min of one-arm cranking and 8h walking/day). Muscle biopsies from both deltoid and one vastus lateralis were taken before (PRE), after CR+PE and following 3 days of control diet (isoenergetic) and reduced exercise (CD). Plasma renin and aldosterone were measured. ACE1, ACE2, AT1R, and AT2R protein expression were analysed (Western Blot). Body composition was assessed by DEXA. Statistics: Repeated-measures ANOVA. RESULTS: After CR+PE, the energy deficit was 5500 kcal/d, reducing fat-free mass (FFM) (P<0.001). Legs and trained arm lost proportionally less FFM than the untrained arm [57% (P<0.05) and 29% (P=0.05), respectively]. Plasma aldosterone and renin significantly increased after CR+PE, and to a greater extent in the whey protein group (interaction, P<0.05). The basal expression of ACE1 and ACE2 was higher in arms than legs (P<0.001). ACE1 and ACE2 expression were increased from PRE to CR+PE and even further from PRE to CD. ACE2 (mean of both arms) was similarly increased in both groups from PRE to CR+PE and PRE to CD, but this response was blunted in the legs (interaction P=0.035). AT1R was more expressed in legs than arms (P<0.05) and did not change with the intervention. AT2R was similarly reduced in all muscles from PRE to CR+PE (P=0.04), remaining lowered after CD. CONCLUSION: During severe energy deficit, RAS signalling is upregulated in human arm muscles via markedly increased expression of ACE1 and ACE2. This was accompanied by a proportionally higher loss of muscle mass in the arm than the legs. In turn, in the legs, there was no-upregulation of ACE2. Some studies have shown that angiotensin receptor blockers may attenuate SM atrophy due to disuse and facilitate muscle regeneration after orthopaedic trauma. The fact that the subjects who ingested only whey protein lost more SM mass (1) and displayed more activation of circulating RAS also points in this direction. Altogether, this study indicates that a high volume of exercise, like that performed by the legs blunt the local upregulation of RAS, what could explain the sparing effect of exercise on lean mass. New studies should determine whether pharmacological inhibition of RAS may help to spare muscle mass during severe energy deficit.