The International Journal of Biochemistry & Cell Biology
ReviewSkeletal muscle RAS and exercise performance
Introduction
Renin cleaves angiotensinogen to generate the non-pressor decapeptide angiotensin I (Ang I). The octapeptide angiotensin II (Ang II) is then derived primarily by the action of angiotensin-converting enzyme (ACE) which may either be circulating (after release by a carboxypeptidase) or an integral membrane protein (Beldent, Michaud, Wei, Chauvet, & Corvol, 1993; Zisman, 1998). ACE also catalyses inactivation of bradykinin (BK) and in this context is known as kininase II. Thus, ACE simultaneously generates a potent vasoconstrictor (Ang II) and inactivates a potent vasodilator (BK).
Our original concept of a circulating renin–angiotensin system (RAS) producing Ang II has altered as our knowledge about the function, receptors and existence of other effector peptides (Ang-(1–7), Ang III and Ang IV) generated by the RAS has developed. In addition, the existence of a local RAS has been established in several tissues and our understanding as to their role continues. Recent data implicate a skeletal muscle RAS with local de novo angiotensin II production and intrinsic ACE activity that is physiologically responsive. Moreover, pharmacological manipulation of specific aspects of the RAS in addition to genetic studies suggest that a muscle RAS may have significant functional implications in regard to human performance.
Section snippets
Local renin–angiotensin systems
A local RAS may be suggested by evidence of gene expression of RAS components within the tissue as well as physiological responsiveness of this gene expression. In addition, local generation of Ang II and the presence of Ang II receptors that are physiologically active (i.e. demonstration of the effects of both Ang II and Ang II receptor antagonists on the tissue) are important. These criteria have been variously met and local RAS have been described in adipose tissue (Jonsson, Game, Head, &
Human performance and the muscle RAS
Information regarding the effect of skeletal muscle RAS on human exercise performance is currently derived from two main sources: the effects of drugs specifically inhibiting aspects of the RAS, and genetic studies of the RAS.
Potential mechanisms by which skeletal muscle RAS may affect performance
AT1-mediated Ang II is crucial for optimal overload-induced skeletal muscle hypertrophy (Gordon, Davis, Carlson, & Booth, 2001). In surgically-induced plantaris and/or soleus muscle overload inhibiting endogenous Ang II production by ACE inhibition markedly attenuates muscle hypertrophy which is restored by local Ang II perfusion. AT1 receptor antagonism also attenuates hypertrophy but is not rescued by Ang II perfusion. It is locally elevated Ang II that is vital since the contralateral soleus
Conclusion
A physiologically functional skeletal muscle RAS exists. It is capable of de novo angiotensin II production and interaction with the kallikrein–kinin system. As such there is significant potential for an influence on human performance. Pharmacological and genetic studies support an active role for paracrine RAS in determining our final performance. This has implications not just for elite athletes but for further pharmacological manipulation of any disease state where muscle function is
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