Myocardial fibrosis is unaltered by long-term administration of l-arginine in dystrophin deficient mdx mice: a histomorphometric analysis

Páginas: 12 (2964 palavras) Publicado: 13 de fevereiro de 2013
Acta Biologica Hungarica 61(2), pp. 168–174 (2010)
DOI: 10.1556/ABiol.61.2010.2.5

Myocardial fibrosis is unaltered
by long-terM adMinistration of l-arginine
in dystrophin deficient mDx Mice:
a histoMorphoMetric analysis
Maria Julia Marques, isabel Cristina Chagas barbin,
ana Paula tieMi taniguti, Daniela silva Oggian,
r. Ferretti and h. santO netO*
Departamento de Anatomia, Institutode Biologia Celular, Fisiologia e Biofisica,
universidade estadual de campinas (unicaMp), cp 6109, 13083-970, campinas, sp, brazil
(Received: May 27, 2009; accepted: July 27, 2009)
Cardiac failure secondary to myocardial fibrosis (MF) significantly contributes to death in Duchenne
muscular dystrophy (DMD), a fatal form of muscle disease. In aging, the mdx mice, an animal model of
DMD, MF issimilar to that observed in humans. Nitric oxide-based therapy has been proposed to retard
MF in DMD and a candidate is L-arginine (L-arg). In this study we evaluated the effects of long-term
therapy with L-arg in the MF of mdx mice. mdx mice (6 months old) were treated with L-arg in drinking
water. Control mdx mice received water only. After 15 months of treatment, hearts were stained withMasson’s trichrome for analysis of MF and with hematoxilyn and eosin for analysis of inflammation and
cardiomyocyte damage. We observed that MF was not affected (29.5 ± 2.5% of MF area for control vs
31.4 ± 2% for L-arginine-treated animals; P > 0.05). The density of inflammatory cells was reduced
(169 ± 12 cells/mm2 in control vs 102 ± 9 cells/mm2 in L-arg-treated; P < 0.05). The present studyshows
that long-term administration of L-arg is not effective in retarding MF in mdx dystrophinopathy.
Keywords: Cardiac failure – cardiac fibrosis – cardiomyopathy – Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common X-linked disease, affecting 1 in 3,500 newborn males. It is a fatal form of muscular dystrophy caused by the
absence of dystrophin, aprotein that supports the plasma membrane in skeletal and
cardiac muscle fibers [11]. One-third of DMD patients show signs of cardiac dysfunction by mid-teenage and virtually all DMD patients develop cardiac dysfunction by
the end of their life. Eventually, 10–40% of DMD patients die from cardiac failure
secondary to progressive accumulation of myocardial fibrosis (MF) [8, 9, 13, 18].
in aging,the mdx mice, an animal model of DMD, exhibit MF similar to that
observed in humans [20]. Loss of dystrophin is accompanied by a decrease of dystrophin-associated proteins, which includes nitric oxide synthase (NOS). Decreased
levels of nitric oxide (NO), secondary to decrease of NOS have been associated with
cardiac involvement and restoration of neural NOS activity was found to limit MF inmdx mice [28]. Hence, NO-based therapy has been proposed to treat MF in DMD and
* Corresponding author; e-mail:
0236-5383/$ 20.00 © 2010 Akadémiai Kiadó, Budapest


L-arginine in dystrophic cardiomyopathy

L-arginine, the substrate for NOS, has emerged as a pharmacological candidate for
that [27, 28].
Lifelong pharmacological therapy is required since there is nodefinitive cure for
DMD and the effect of L-arginine therapy can be beneficial or harmful depending on
the duration of administration [2, 19]. Therefore, the purpose of the present study was
to investigate whether long-term (15 months) oral administration of L-arginine affect
the progression of MF in dystrophin deficient mdx mice.

Experimental design
Experimental procedures wereconducted in strict accordance with guidelines established by the Brazilian College of Animal Experimentation and were approved by our
Institutional Animal Care and Use Committee. Six-month-old male mdx mice were
used (n = 20). Animals were treated with L-arginine (n = 10; L-arg; 2-amino-5guanidinovaleric acid; Sigma, St Louis) in drinking water (8 mg/kg/day). Control
(untreated) mdx mice (n =...
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