Fibrosis inhibition and muscle histopathology improvement in laminin‐α2‐deficient mice

Nevo, Yoram; Halevy, Orna; Genin, Olga; Moshe, Itai; Turgeman, Tidhar; Harel, Michal; Biton, Edva; Reif, Shimon; Pines, Mark

doi:10.1002/mus.21706

Cited by 37 publications

(42 citation statements)

References 61 publications

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“…Our results are similar to those of other researchers who tested inhibition of TGF-β-induced fibrosis by intraperitoneal injection of halofuginone in the milder dy 2J /dy 2J mouse model of MDC1A [36]. Halofuginone blocked TGF-β-mediated collagen synthesis, prevented muscle fibrosis, and improved the performance of both muscles and animals.…”

Section: Discussionsupporting

confidence: 90%

“…These include inhibition of apoptosis in dy W /dy W mice [29-32] and interference with proteasomal and autophagy-mediated degradation of proteins [33,34], Halofuginone, an analog of a plant alkaloid that blocks TGF-β-mediated collagen synthesis, was tested in dy 2J /dy 2J mice, which represent a much milder form of MDC1A that is caused by the partial loss of laminin-211 [35]. In these mice, halofuginone was shown to inhibit Smad3 phosphorylation downstream of TGF-β activation and to prevent progression of fibrosis, resulting in an amelioration of the dystrophic phenotype [36]. Likewise, in dy 2J / dy 2J mice, losartan was shown to inhibit TGF-β signaling, improve grip strength, and reduce fibrosis [37].…”

Section: Introductionmentioning

confidence: 99%

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Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-α2-deficient congenital muscular dystrophy (MDC1A)

2012

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BackgroundLaminin-α2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti-hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-β and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A.MethodsL-158809 was given in food to dyW/dyW mice at the age of 3 weeks, and the mice were analyzed at the age of 6 to 7 weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice.ResultsWe found that TGF-β signaling in the muscles of the dyW/dyW mice was strongly increased, and that L-158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased.ConclusionThese data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best-characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-α2-deficient congenital muscular dystrophy (MDC1A)

2012

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“…This test is a complex motor task requiring muscle coordination and balance, as well as motor learning, and it has been used to determine the effectiveness of treatments for mouse muscular dystrophy models ( 42, 43 ). As expected, Lmna –/– mice were unable to stay on the rotating rod as long as Lmna +/+ mice ( P < 0.05), and they did not reach the same maximum speed as Lmna +/+ mice given the same amount of time ( P < 0.01) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival

et al. 2012

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Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna–/– mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna–/– mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors.

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“…Treatment with Glatiramer Acetate, an immune modulating agent, resulted in significant improvement in hind limb muscle strength, improvement of mouse mobility as well as attenuation of the fibrosis markers vimentin and fibronectinin in dy 2J /dy 2J mice [25]. Halofuginone an anti-fibrotic agent (pro-collagen 1 inhibitor) treatment was associated with fibrosis inhibition in both mdx and dy 2J /dy 2J mice [48]. Losartan treatment resulted in improved muscle regeneration and diminished fibrosis in the mdx mouse by TGF-β antagonism.…”

Section: Discussionmentioning

confidence: 99%

The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

et al. 2011

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The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy2J/dy2J mouse model of merosin deficient congenital muscular dystrophy. The dy2J/dy2J mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy2J/dy2J mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy2J/dy2J mouse model of congenital muscular dystrophy.

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Fibrosis inhibition and muscle histopathology improvement in laminin‐α2‐deficient mice

Cited by 37 publications

References 61 publications

Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-α2-deficient congenital muscular dystrophy (MDC1A)

Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-α2-deficient congenital muscular dystrophy (MDC1A)

Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival

The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

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