Disruption of muscle renin-angiotensin system in AT1a-/- mice enhances muscle function despite reducing muscle mass but compromises repair after injury.

Abstract

The role of the renin-angiotensin system (RAS) in vasoregulation is well established, but a localized RAS exists in multiple tissues and exerts diverse functions including autonomic control and thermogenesis. The role of the RAS in the maintenance and function of skeletal muscle is not well understood, especially the role of angiotensin peptides, which appear to contribute to muscle atrophy. We tested the hypothesis that mice lacking the angiotensin type 1A receptor (AT(1A)(-/-)) would exhibit enhanced whole body and skeletal muscle function and improved regeneration after severe injury. Despite 18- to 20-wk-old AT(1A)(-/-) mice exhibiting reduced muscle mass compared with controls (P < 0.05), the tibialis anterior (TA) muscles produced a 25% higher maximum specific (normalized) force (P < 0.05). Average fiber cross-sectional area (CSA) and fiber oxidative capacity was not different between groups, but TA muscles from AT(1A)(-/-) mice had a reduced number of muscle fibers as well as a higher proportion of type IIx/b fibers and a lower proportion of type IIa fibers (P < 0.05). Measures of whole body function (grip strength, rotarod performance, locomotor activity) were all improved in AT(1A)(-/-) mice (P < 0.05). Surprisingly, the recovery of muscle mass and fiber CSA following myotoxic injury was impaired in AT(1A)(-/-) mice, in part by impaired myoblast fusion, prolonged collagen infiltration and inflammation, and delayed expression of myogenic regulatory factors. The findings support the therapeutic potential of RAS inhibition for enhancing whole body and skeletal muscle function, but they also reveal the importance of RAS signaling in the maintenance of muscle mass and for normal fiber repair after injury.

• Authors: Kate T Murphy, Andrew M Allen, Annabel Chee, Timur Naim, Gordon S Lynch
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 303 Issue 3 Pg. R321-31 (Aug 01 2012) ISSN: 1522-1490 [Electronic] United States
• PMID: 22673782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type II
• Elapid Venoms
• Receptor, Angiotensin, Type 1
• notexin

Topics

• Animals
• Collagen Type II (physiology)
• Elapid Venoms (adverse effects, pharmacology)
• Male
• Mice
• Mice, Knockout
• Models, Animal
• Muscle Fibers, Skeletal (pathology, physiology)
• Muscle Strength (physiology)
• Muscle, Skeletal (drug effects, injuries, physiopathology)
• Muscular Atrophy (pathology, physiopathology)
• Receptor, Angiotensin, Type 1 (deficiency, genetics)
• Renin-Angiotensin System (physiology)
• Signal Transduction (physiology)
• Wound Healing (physiology)