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. Author manuscript; available in PMC: 2011 Jul 18.
Published in final edited form as: Nat Med. 2007 Jan 21;13(2):204–210. doi: 10.1038/nm1536

Figure 4.

Figure 4

Losartan decreases angiotensin II-mediated TGF-β signaling and improves muscle function in mdx mice. (a) Immunofluorescence analysis of target proteins downstream of the AT1. The diaphragm of mdx mice shows increased expression of thrombospondin-1 (TSP-1), a potent activator of TGF-β, and increased nuclear accumulation of pSmad2 and sarcolemmal and matrix expression of peripostin, when compared to wild-type or losartan-treated mdx mice. The inset box shows nuclear accumulation of pSmad2 in a connective tissue-rich region of diseased muscle. Scale bar, 100 μm. (b) Long-term losartan treatment attenuated myopathic disease progression in 9 month-old mdx mice. Representative sections of van Gieson–stained diaphragm from wild-type, mdx and losartan-treated mdx mice. Losartan-treated mice showed significantly (P 0.03) less fibrosis (red) than untreated mdx mice. Scale bar, 150 μm. The graphs show quantification of fibrotic area, expressed as percentage of total muscle area (left), and minimal Feret’s diameter variance coefficient (right). (c) In vitro force-frequency relationship of explanted EDL muscle. Isometric tension (g) versus stimulation frequency (1–150 Hz) was reduced in mdx mice at frequencies equal to or greater than 60 Hz, but was fully restored in losartan-treated mdx mice, as compared to wild-type animals (*wild-type versus mdx mice, **losartan-treated versus untreated mdx mice, P < 0.05; left graph). When force was normalized to muscle cross-sectional area (relative tension), losartan-treated mdx and wild-type mice were indistinguishable, whereas untreated mdx mice showed a significant decrease at frequencies of 100 and 150 Hz, when compared to either wild-type or losartan-treated mdx mice, (*wild-type versus mdx mice, **losartan-treated versus untreated mdx mice, P < 0.05; right graph). Representative low-power whole-muscle montages of EDL muscles from two untreated mdx mice (left) showed an overall decrease in muscle size and fiber content and an increase in fibrosis, as compared to two losartan-treated mdx mice (right). Wild-type mice, n = 4; untreated mdx mice, n = 3; losartan-treated mdx mice, n = 4. Scale bar, 150 μm.