Angiotensin II Receptor Blockade Administered after Injury Improves Muscle Regeneration and Decreases Fibrosis in Normal Skeletal Muscle

Abstract

Background:

Several therapeutic agents have been shown to inhibit fibrosis and improve regeneration after injury in skeletal muscle by antagonizing transforming growth factor-β1. Angiotensin receptor blockers have been shown to have a similar effect on transforming growth factor-β1 in a variety of tissues.

Hypothesis:

Systemic treatment of animals after injury of skeletal muscle with an angiotensin receptor blocker may decrease fibrosis and improve regeneration, mainly through transforming growth factor-β1 blockade, and can be used to improve skeletal muscle healing after injury.

Study Design:

Controlled laboratory study.

Methods:

Forty mice underwent bilateral partial gastrocnemius lacerations. Mice were assigned randomly to a control group (tap water), a low-dose angiotensin receptor blocker group (losartan, 0.05 mg/mL), or a high-dose angiotensin receptor blocker group (0.5 mg/mL). The medication was dissolved in tap water and administered enterally. Mice were sacrificed 3 or 5 weeks after injury, and the lacerated muscles were examined histologically for muscle regeneration and fibrosis.

Results:

Compared with control mice at 3 and 5 weeks, angiotensin receptor blocker–treated mice exhibited a histologic dose-dependent improvement in muscle regeneration and a measurable reduction in fibrous tissue formation within the area of injury.

Conclusion:

By modulating the response to local and systemic angiotensin II, angiotensin receptor blocker therapy significantly reduced fibrosis and led to an increase in the number of regenerating myofibers in acutely injured skeletal muscle. The clinical implications for this application of angiotensin receptor blockers are potentially far-reaching and include not only sports- and military-related injuries, but also diseases such as the muscular dystrophies and trauma- and surgery-related injury.

Clinical Relevance:

Angiotensin receptor blockers may provide a safe, clinically available treatment for improving healing after skeletal muscle injury.

Keywords

fibrosis angiotensin receptor blocker TGF-β muscle injury muscle regeneration

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References

Almekinders

. Anti-inflammatory treatment of muscular injuries in sports. Sports Med. 1993;15(3):139–145.

American Academy of Family Physicians. ICD-9 Codes for Family Medicine 2005–2006. 2005.

Aronson Jeffrey

. Angiotensin II receptor antagonists. In: Aronson

, ed. Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. Amsterdam: Elsevier; 2006:223–226.

Bedair

Huard

. Angiotensin receptor blockers improve muscle regeneration and decrease fibrosis in injured skeletal muscle. Trans Orthop Res Soc. 2005;30:524.

Bedair

Liu

Kaar

. Matrix metalloproteinase-1 therapy improves muscle healing. J Appl Physiol. 2007;102:2338–2345.

Best

Shehadeh

Leverson

Michel

Corr

Aeschlimann

. Analysis of changes in mRNA levels of myoblast- and fibroblast-derived gene products in healing skeletal muscle using quantitative reverse transcription-polymerase chain reaction. J Orthop Res. 2001; 19(4):565–572.

Bosch

. Losartan-induced acute pancreatitis. Ann Intern Med. 1997;127:1043–1044.

Bosch

. Losartan-induced hepatotoxicity. JAMA. 1997;278:1572.

Chan

Foster

. Antifibrotic effects of suramin in injured skeletal muscle after laceration. J Appl Physiol. 2003;95(2):771–780.

10.

Cohn

van Erp

Habashi

. Angiotensin II type 1 receptor blockade attenuates TGF-β-induced failure of muscle regeneration in multiple myopathic states. Nat Med. 2007;13(2):204–210.

11.

Cozaar [package insert]. West Point, PA: Merck & Co Inc;1995.

12.

Folland

Leach

Little

. Angiotensin-converting enzyme genotype affects the response of human skeletal muscle to functional overload. Exp Physiol. 2000;85(05):575–579.

13.

Foster

Usas

Somogyi

Huard

. Gamma interferon as an antifibrosis agent in skeletal muscle. J Orthop Res. 2003;21(5):798–804.

14.

Fukushima

Badlani

Usas

Riano

Huard

. The use of an antifibrosis agent to improve muscle recovery after laceration. Am J Sports Med. 2001;29(4):394–402.

15.

Gremmler

Kunert

Schleiting

Ulbricht

. Improvement of cardiac output in patients with severe heart failure by use of ACE-inhibitors combined with the AT1-antagonist eprosartan. Eur J Heart Fail. 2000;2(2):183–187.

16.

Huard

. Muscle injuries and repair: Current trends in research. J Bone Joint Surg Am. 2002;84(5):822–832.

17.

Hurme

Kalimo

Lehto

Jarvinen

. Healing of skeletal muscle injury: An ultrastructural and immunohistochemical study. Med Sci Sports Exerc. 1991;23(7):801–810.

18.

Jarvinen

Lehto

. The effects of early mobilization and immobilization on the healing process following muscle injuries. Sports Med. 1993;15(2):78–89.

19.

Kalimo

Rantanen

Jarvinen

. Muscle injuries in sports. Baillieres Clin Orthop. 1997;2:1–24.

20.

Kherif

Lafuma

Dehaupas

. Expression of matrix metallo proteinases 2 and 9 in regenerating skeletal muscle: A study in experimentally injured and mdx muscles. Dev Biol. 1999;205(1):158–170.

21.

Huard

. Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle. Am J Pathol. 2002;161(3):895–907.

22.

Negishi

Sakamoto

Usas

Huard

. The use of relaxin improves healing in injured muscle. Ann N Y Acad Sci. 2005:1041: 395–397.

23.

Lim

Lutucuta

Bachireddy

. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation. 2001;103(6)789–791.

24.

Negishi

Usas

Huard

. The effect of relaxin treatment on skeletal muscle injuries. Am J Sports Med. 2005;33(12):1816–1824.

25.

Onder

Vedova

Pahor

. Effects of ACE inhibitors on skeletal muscle. Curr Pharm Des. 2006;12(16):2057–2064.

26.

Orchard

Best

. The management of muscle strain injuries: An early return versus the risk of recurrence. Clin J Sport Med. 2002;12(1):3–5.

27.

Otsuka

Takahashi

Shiratori

Chiba

Abe

. Reduction of bleomycin-induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist. Thorax. 2004;59(1):31–38.

28.

Paizis

Gilbert

Cooper

. Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol. 2001;35(3):376–385.

29.

Qu-Petersen

Deasy

Jankowski

. Identification of a novel population of muscle stem cells in mice: Potential for muscle regeneration. J Cell Biol. 2002;157(5):851–864.

30.

Suga

Mazzali

Ray

Kang

Johnson

. Angiotensin II type 1 receptor blockade ameliorates tubulointerstitial injury Induced by chronic potassium deficiency. Kidney Int. 2002;61(3):951–958.

31.

Swedberg

Kjekshus

. Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol. 1988;62(2):60A–66A.

32.

Woods

Hawkins

Maltby

. The Football Association Medical Research Programme: An audit of injuries in professional football—analysis of hamstring injuries. Br J Sports Med. 2004; 38(1):36–41.

33.

Worrell

. Factors associated with hamstring injuries. An approach to treatment and preventative measures. Sports Med. 1994;17(5): 338–345.