[h=1]PROGRESS IN VALIDATION OF MYOSTATIN AS A TARGET FOR MUSCLE WASTING DISORDERS[/h]
Preclinical results
Two recent studies, performed in mouse models of cancer cachexia, have examined the effects of myostatin inhibitors on physical performance and muscle function, building on previous data that showed positive effects on muscle mass [30,31]. Mice with Lewis Lung carcinoma treated with ActRIIB-Fc (Fig. 1), a soluble myostatin receptor that binds myostatin, activin and other ligands, showed increases in body weight and muscle weights with grip strength significantly increased and resting time significantly decreased by treatment [32▪]. A myostatin antibody in the same model was able to completely abrogate the tumor-induced reduction in total muscle force in various limb and diaphragm muscles [33▪]. The results of these recent studies are encouraging as the value of myostatin inhibitors to cancer patients exhibiting muscle wasting is ultimately to affect functional performance through increased muscle function.
Aside from models of cancer cachexia, most recently published preclinical activity with myostatin inhibitors has focused on developing therapies in the area of rare or orphan diseases, in which symptoms are devastating to patients and few if any significant treatment options are available. Testing of myostatin inhibitors in animal models of muscular dystrophy [34] has shown generally positive effects on muscle mass but inconsistent effects on muscle function and histopathology [reviewed in [35▪]]. ActRIIB-Fc or ActRIIB shRNA given to mdx mice, a well used but not ideal model of human muscular dystrophy[36,37▪▪], produced increases in muscle mass and total force but specific force was unchanged [38,39▪,40]. In contrast, a recent study reported an increase in specific force of the soleus muscle in mdx mice after long-term exposure to a myostatin propeptide [41]. Studies with myostatin inhibitors have not shown any improvement on eccentric contraction-induced force drop, a key measure of myofiber structural integrity[40,42,43]. Therefore, there is increasing evidence that myostatin inhibitors can improve muscle function in the mdx mouse through an increase in muscle mass and total force but do not consistently improve the underlying weakness of dystrophic muscle. There has been hope that myostatin inhibitors might attenuate the muscle fibrosis that is a hallmark of muscular dystrophy, given myostatin's role in inducing dystrophic muscle fibroblast proliferation [44▪] and the observation of decreased connective tissue in myostatin null mice [45▪]. Although earlier observations in mdx mice [34] and more recent observations in the golden retriever muscular dystrophy model [GRMD [46]], showed improvement in fibrosis with myostatin antibody or myostatin propeptide treatment, respectively, no improvement on muscle histopathology was seen after ActRIIB-Fc treatment of mdx mice [40,42]. It has been suggested that the degree of muscle disease at the time of treatment may influence outcome [43]. Human muscular dystrophy disorders display paradoxical muscle wasting and selective hypertrophy of skeletal muscles, leading to imbalance, contractures and postural instabilities [37▪▪]. When the muscle hypertrophic myostatin heterozygote whippet [47] was crossed with the GRMD dog, selective muscle hypertrophy seen in the GRMD dog was exaggerated resulting in more pronounced postural instability and worsened clinical scores, cautioning that further hypertrophy of already selective hypertrophic muscle in muscular dystrophy may not be beneficial[37▪▪]. Dysferlin null mice, a model of dysferlin-deficiency muscular dystrophy [48], expressing the myostatin inhibitor follistatin, demonstrated a transient increase in muscle mass followed by decreased muscle mass and function and increased muscle fibrosis [Lee et al. MDA meeting, San Diego, 2013].
There is excitement regarding disease-modifying therapies currently in clinical development for muscular dystrophy based on exon skipping methods, which overcome the underlying genetic defect of the dystrophin gene and improve specific muscle force without effects on muscle mass [reviewed in [49,50]]. Myostatin inhibitors are currently being investigated preclinically as possible adjunct therapy with these molecules [39▪,42,51–53].
The recently described increase in axon number together with delay in age-related neural degeneration in myostatin null mice have added support to the investigation of myostatin inhibitors for the treatment of severe neuromuscular disorders [54▪,55]. However, SOD1 null mice, a model of amyotrophic lateral sclerosis, did not exhibit any improvements in survival (despite improvements in muscle mass) when exposed to myostatin inhibitors [56]. In another report, crossing of SMN null mice, a model of Spinal Muscular Atrophy, with myostatin null mice did not lead to increases in muscle mass or effects on survival[57], consistent with results using myostatin inhibitors from Sumner et al. [58] but inconsistent with the positive effects reported by Rose et al. [59]. In contrast to the above reports, treatment of the myotubularin-deficient mouse, a model of X-linked myotubular myopathy, with ActRIIB-Fc did lead to transient increases in muscle mass and strength and a 17% increase in survival [60▪▪].
Other animal models of muscle wasting have been used to determine if inhibition of myostatin has therapeutic potential in treating a range of muscle wasting conditions. Positive results have been reported in models of chronic kidney disease, disuse atrophy and age and hypogonadism-induced muscle loss[61,62▪,63]. Overexpression of the myostatin interacting protein GASP1 [64] has been shown to induce muscular hypertrophy in mice but has not yet been tested in models of muscle wasting. Identification of myostatin-blocking decorin peptides are at an even earlier stage of preclinical development [65]. There is increasing preclinical evidence to suggest that inhibition of myostatin may also have metabolic benefits. Myostatin deficiency or myostatin inhibition in mice has been shown to result in decreased fat mass and increased insulin sensitivity raising the therapeutic potential of myostatin inhibition in obesity and insulin resistance associated with obesity [reviewed in [23]].
