jomi822
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Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6085, USA.
Mutations in myostatin (GDF8) cause marked increases in muscle mass, suggesting that this transforming growth factor-beta (TGF-beta) superfamily member negatively regulates muscle growth. Myostatin blockade therefore offers a strategy for reversing muscle wasting in Duchenne's muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate that pharmacological blockade using a myostatin propeptide stabilized by fusion to IgG-Fc improved pathophysiology of the mdx mouse model of DMD. Functional benefits evidenced by specific force improvement, exceeded those reported previously using myostatin antibody-mediated blockade. More importantly, use of a propeptide blockade strategy obviates possibilities of anti-idiotypic responses that could potentially limit the effectiveness of antibody-mediated myostatin blockade strategies over time. This study provides a novel pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD and since it uses an endogenous inhibitor of myostatin should help circumvent technical hurdles and toxicity associated with conventional gene or cell based therapies.
Full Report-http://www.fasebj.org/cgi/content/full/19/6/543#B42
Discussion Portion
Correction of the muscle wasting pathognomic of DMD constitutes an important goal for a variety of therapeutic strategies (11 12 13 , 40 , 41) . It is becoming increasingly apparent that this can be achieved not only by positive effectors of muscle growth (e.g., IGF-1) (42 , 43) , but also via repression of "negative" growth factors such as myostatin (GDF8) (19 , 21) , which inhibit muscle growth. We used the latter strategy in this study to demonstrate that myostatin blockade achieved by i.p. injections of a stabilized version of the myostatin propeptide resulted in a functional improvement of dystrophic pathophysiology in mdx mice. This strategy provides a novel pharmacological approach for treatment of diseases associated with muscle wasting and circumvents technical hurdles and toxicity associated with conventional gene or cell-based therapy. The use of this endogenously expressed molecule obviates the possibility of an anti-idiotypic response that could potentially limit effectiveness of antibody-mediated myostatin blockade strategy (19) over time. As sequence information for canine (K. J. Perkins and T. S. Khurana; AY367768) and human (19 , 25) myostatin is available, species-specific propeptide molecule(s) can be readily generated for conducting preclinical studies in the canine DMD model. If issues regarding the significantly higher costs, breeding difficulties, and phenotypic variability associated with the canine model can be satisfactorily circumvented by experimental design, preclinical testing of the myostatin propeptide approach in dystrophic dogs could facilitate efficient progression to clinical studies in patients, since the progressive muscle weakness and fibrosis observed for the canine DMD model more closely resembles human DMD than mice. In princi-ple, synthesis of therapeutic propeptide molecules would overcome the potential delays and difficulties associated with identification and isolation of functional canine or humanized antibodies against myostatin for use in these species.
The degree of physiological improvement achieved using the propeptide approach exceeded the improvement achieved using murine antibody-mediated blockade (19) , as evidenced by an improvement in specific force (Table 2 ). This may be related to the 500-fold higher binding affinity of the propeptide moiety to myostatin compared with the blocking antibodies and/or the potential for the propeptide moiety to target GDF8 (myostatin) and closely related GDF11, rather than GDF8 alone. Improvement of specific force is a significant finding since it provides physiological evidence of a fundamental improvement in muscle mechanics using this pharmacological strategy. Though extremely encouraging, it is important to point out that no improvement was observed when using provocative ex vivo lengthening contraction protocols (Table 1) , suggesting that the muscle remained susceptible to contraction-mediated damage (27 , 28) . This may be related to late onset and/or inadequate dosage of propeptide or a shared feature of strategies that seek to increase muscle mass in order to compensate for the dystrophic phenotype rather than directly replace the missing gene product (19 , 37 , 42 , 43) . These limitations could be overcome by combinatorial use with conventional gene/cell-based therapies or pharmacological approaches designed to correct specific functional deficits (44) . The fact that such significant benefits were achieved independent of increased utrophin expression suggests that myostatin blockade could be further potentiated by combination with effectors of utrophin up-regulation known to improve ECC force drop (13 , 29 , 45) . Experiments are currently under way to test these possibilities
Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6085, USA.
Mutations in myostatin (GDF8) cause marked increases in muscle mass, suggesting that this transforming growth factor-beta (TGF-beta) superfamily member negatively regulates muscle growth. Myostatin blockade therefore offers a strategy for reversing muscle wasting in Duchenne's muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate that pharmacological blockade using a myostatin propeptide stabilized by fusion to IgG-Fc improved pathophysiology of the mdx mouse model of DMD. Functional benefits evidenced by specific force improvement, exceeded those reported previously using myostatin antibody-mediated blockade. More importantly, use of a propeptide blockade strategy obviates possibilities of anti-idiotypic responses that could potentially limit the effectiveness of antibody-mediated myostatin blockade strategies over time. This study provides a novel pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD and since it uses an endogenous inhibitor of myostatin should help circumvent technical hurdles and toxicity associated with conventional gene or cell based therapies.
Full Report-http://www.fasebj.org/cgi/content/full/19/6/543#B42
Discussion Portion
Correction of the muscle wasting pathognomic of DMD constitutes an important goal for a variety of therapeutic strategies (11 12 13 , 40 , 41) . It is becoming increasingly apparent that this can be achieved not only by positive effectors of muscle growth (e.g., IGF-1) (42 , 43) , but also via repression of "negative" growth factors such as myostatin (GDF8) (19 , 21) , which inhibit muscle growth. We used the latter strategy in this study to demonstrate that myostatin blockade achieved by i.p. injections of a stabilized version of the myostatin propeptide resulted in a functional improvement of dystrophic pathophysiology in mdx mice. This strategy provides a novel pharmacological approach for treatment of diseases associated with muscle wasting and circumvents technical hurdles and toxicity associated with conventional gene or cell-based therapy. The use of this endogenously expressed molecule obviates the possibility of an anti-idiotypic response that could potentially limit effectiveness of antibody-mediated myostatin blockade strategy (19) over time. As sequence information for canine (K. J. Perkins and T. S. Khurana; AY367768) and human (19 , 25) myostatin is available, species-specific propeptide molecule(s) can be readily generated for conducting preclinical studies in the canine DMD model. If issues regarding the significantly higher costs, breeding difficulties, and phenotypic variability associated with the canine model can be satisfactorily circumvented by experimental design, preclinical testing of the myostatin propeptide approach in dystrophic dogs could facilitate efficient progression to clinical studies in patients, since the progressive muscle weakness and fibrosis observed for the canine DMD model more closely resembles human DMD than mice. In princi-ple, synthesis of therapeutic propeptide molecules would overcome the potential delays and difficulties associated with identification and isolation of functional canine or humanized antibodies against myostatin for use in these species.
The degree of physiological improvement achieved using the propeptide approach exceeded the improvement achieved using murine antibody-mediated blockade (19) , as evidenced by an improvement in specific force (Table 2 ). This may be related to the 500-fold higher binding affinity of the propeptide moiety to myostatin compared with the blocking antibodies and/or the potential for the propeptide moiety to target GDF8 (myostatin) and closely related GDF11, rather than GDF8 alone. Improvement of specific force is a significant finding since it provides physiological evidence of a fundamental improvement in muscle mechanics using this pharmacological strategy. Though extremely encouraging, it is important to point out that no improvement was observed when using provocative ex vivo lengthening contraction protocols (Table 1) , suggesting that the muscle remained susceptible to contraction-mediated damage (27 , 28) . This may be related to late onset and/or inadequate dosage of propeptide or a shared feature of strategies that seek to increase muscle mass in order to compensate for the dystrophic phenotype rather than directly replace the missing gene product (19 , 37 , 42 , 43) . These limitations could be overcome by combinatorial use with conventional gene/cell-based therapies or pharmacological approaches designed to correct specific functional deficits (44) . The fact that such significant benefits were achieved independent of increased utrophin expression suggests that myostatin blockade could be further potentiated by combination with effectors of utrophin up-regulation known to improve ECC force drop (13 , 29 , 45) . Experiments are currently under way to test these possibilities
