Angiotensin II
Type 1 Receptor Blockade Improves TGFb-induced Failure
of Muscle Regeneration in the mdx Mouse Model of Duchenne Muscular Dystrophy.
R.D. Cohn,
J.P. Habashi, B.L. Loeys, E.C. Klein, M. Gamradt, T.M. Holm, D.P. Judge, H.C.
Dietz USA
We have previously shown that increased TGFb activity
causes abnormal muscle regeneration and myopathy in fibrillin-1 deficient mice,
a model of Marfan syndrome. Systemic antagonism of TGFb via
administration of TGFb-neutralizing antibody or the angiotensin II type 1
receptor (AT1) blocker losartan restores abnormal muscle regeneration and
prevents subsequent development of myopathic features. Impaired satellite cell
performance and muscle repair has also been shown to play a significant role in
the disease progression of various forms of muscular dystrophy. Here we
demonstrate that myopathic changes in the dystrophin-deficient mdx mouse model
of Duchenne muscular dystrophy associates with excessive TGFb signaling,
as evidenced by increased phosphorylation of pSmad2/3. Systemic TGFb antagonism
via losartan improves the satellite cell response to toxin induced-injury in
the mdx mouse. Losartan treated mdx mice have improved steady-state muscle
architecture and a near-normal amount of actively regenerating, neonatal myosin
positive fibers four days after induced injury. After 18 days, losartan-treated
mdx mice show only minimal amount of fibrosis, as demonstrated by vimentin
expression, when compared to placebo-treated mice. Moreover, long-term
administration of losartan leads to improved functional performance as
demonstrated by increased muscle grip strength and decreased muscle fatigue in
mdx mice. Together, our data demonstrate that treatment with the FDA approved
medication losartan attenuates TGFb-induced failure of muscle regeneration and
represents a promising therapeutic strategy for the treatment of Duchenne
muscular dystrophy. Given that losartan is widely used to treat hypertension
and has an exceptional tolerance profile in all age groups, we propose that a
clinical trial using losartan is warranted.