Therefore, glucocorticoids interfere with potential muscle mass benefits associated with targeting Mstn, and the ramifications of glucocorticoid use should be a consideration during clinical trial design for DMD therapeutics.
In young mdx mice, combined dystrophin and myostatin exon skipping therapy greatly improved DMD pathology, compared to the single dystrophin skipping approach.
Model parameters were predicted with high-precision pharmacokinetics (clearance 1.01 × 10<sup>-4</sup> L/[h·kg]; central volume of distribution 457 × 10<sup>-4</sup> L/kg; maximum elimination rate 17.5 × 10<sup>-4</sup> nmol/[h·kg], Km 10.6 nmol/L) and pharmacodynamics (myostatin turnover rate 457 × 10<sup>-4</sup> h<sup>-1</sup> ; complex removal rate 90 × 10<sup>-4</sup> h<sup>-1</sup> ; half-saturation constant 4.32 nmol/L) and were used to predict target coverage for dosage selection in the DMD population.
Moreover, myostatin inhibitors are known to promote muscle regeneration and ameliorate fibrosis in animal models of Duchenne muscular dystrophy (DMD), a human disease characterized by chronic muscle degeneration.
Here we describe the methodology for the systemic intravenous delivery of AOs targeting dystrophin and myostatin in mdx mice, a DMD mouse model, in order to express dystrophin while downregulating myostatin, aiming for an increase in the muscle size and muscle strength.
Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p < 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients.
The premise of this approach is that disruption of myostatin expression is known to induce muscle hypertrophy and so for Duchenne muscular dystrophy (DMD) could be expected to have a better outcome than dystrophin restoration alone.
Inhibition of NF-KB, transforming growth factor-alpha (TGF-α) and transforming growth factor-beta (TGF-β)/myostatin production or action are also promising routes in counteracting the complex pathogenesis of DMD.
Principal differences included a significantly greater proliferation rate and soluble collagen production, a significant upregulation of decorin, myostatin and MMP-7 transcripts and proteins, and a significant downregulation of MMP-1 and TIMP-3 transcripts (with MMP-1 protein being reduced as shown by enzyme-linked immunosorbent assay and TIMP-3 protein apparently being reduced on Western blot), in untreated DMD fibroblasts compared with controls.
Systemic myostatin inhibition led to increased skeletal muscle mass and strength in control C57 Bl/6 mice and in the dystrophin-deficient mdx model of Duchenne muscular dystrophy.
Myostatin inhibition by follistatin in combination with myoblast transplantation is thus a promising novel therapeutic approach for the treatment of muscle wasting in diseases such as Duchenne muscular dystrophy.
Our findings that myostatin-potent inhibitor of satellite cell activation and muscle renewal--is increased, and that decorin-binder and downregulator of TGFbeta1 and myostatin--is decreased, may have implications for DMD therapy to reduce muscle fibrosis.
Inhibition of Myostatin activity in mdx mouse, the animal model for Duchenne muscular dystrophy, resulted in increased force production and better tissue architecture which implicated Myostatin as a target for new therapeutic strategies.
Here, we will review present pharmacological strategies, in particular those dealing with functional substitution of dystrophin by utrophin and enhancing muscle progenitor commitment by myostatin blockade, with a view toward facilitating drug discovery for DMD.