Efficacy of losartan and growth hormone combinatorial therapy in DyW mice
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Merosin-deficient CMD type 1A (MDC1A) is the second most common form of congenital muscular dystrophy (CMD) that presents at or near birth. MDC1A is caused by a mutation in the LAMA2 gene which encodes a protein called laminin-2. The clinical manifestations of MDC1A include profound muscle weakness, muscle hypotonia, loss of independent ambulation, and respiratory failure. There is still no cure or effective treatment available for MDC1A patients. In this study we use the Lama2dyW (DyW) mouse model which shares analogous phenotypes with the MDC1A disease in humans. To this point, therapy development has mainly utilized single-mode therapy. While effective in attenuating some aspects of pathology, no single treatment has been able to completely ameliorate the multi-faceted pathology of laminin-2 deficiency. Therefore this study utilizes a combinatorial treatment strategy with Losartan and Growth Hormone to target multiple pathologies simultaneously. Losartan, an angiotensin II type 1 (AT1) receptor antagonist, is commonly used in hypertensive patients for its abilities to induce vasodilation. In the context of dystrophy, blocking AT1 receptor with losartan inhibits AT1-mediated TGF- signaling leading to decreased fibrosis, normalized muscle architecture, and improved muscle function and regeneration. Losartan does not, however, induce weight gain in models of muscular dystrophy. Growth hormone (GH) is well known to stimulate postnatal skeletal muscle growth as well as overall body weight mainly through Insulin-like Growth Factor 1 (IGF-1). IGF-1 induces muscle growth via Akt-mediated mTOR activation leading to increases in protein synthesis and consequent muscle fiber hypertrophy. Thus we hypothesize that the combination of Losartan and GH would alleviates chronic inflammation and fibrosis as well as induce weight/muscle gain in DyW mice. Dual treatment led to significant gains in total body weight as well as muscle function. In addition to the improvements of weights and activities, dual-treated mice showed a more normalized distribution of fiber size without increased total fiber number suggesting that dual treatment led to muscle hypertrophy not seen in untreated or Losartan-treated DyW mice. Myogenesis associated genes, and specifically late markers of myogenic differentiation were also significantly upregulated in dual-treated mice indicating a more complete and robust myogenic repair compared to untreated and Losartan-treated DyW mice, respectively. Dual treatment also led to increased expression of IGF-1 and IGF-1R as well as the glucose transporter glut4 suggesting that this strategy also affects insulin signaling. This study suggests that a combinatorial anti-fibrotic and pro-myogenic therapy achieves a more comprehensive amelioration of downstream pathologies greater than single-mode therapies and may be a more suitable treatment regimen for complex pathologies such as MDC1A.