The elusive promise of myostatin inhibition for muscular dystrophy

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcome measures selected: the myostatin inhibition story, thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models have failed to translate into clinical benefit to patients have been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.

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Myostatin inhibition promotes fast fibre hypertrophy but causes loss of AMP‐activated protein kinase signalling and poor exercise tolerance in a model of limb‐girdle muscular dystrophy R1/2A

The Journal of Physiology ◽

10.1113/jp279943 ◽

2020 ◽

Vol 598 (18) ◽

pp. 3927-3939 ◽

Cited By ~ 1

Author(s):

Irina Kramerova ◽

Masha Marinov ◽

Jane Owens ◽

Se‐Jin Lee ◽

Diana Becerra ◽

...

Keyword(s):

Protein Kinase ◽

Muscular Dystrophy ◽

Exercise Tolerance ◽

Limb Girdle Muscular Dystrophy ◽

Fast Fibre ◽

Myostatin Inhibition ◽

Amp Activated Protein Kinase ◽

Protein Kinase Signalling

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Regulation of the calpain and ubiquitin proteasome system in a canine model of muscular dystrophy with myostatin inhibition

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.478.3 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Steven W. Cotten ◽

Kristine M. Wadosky ◽

Dan Bogan ◽

Joe N. Kornegay ◽

Monte S. Willis

Keyword(s):

Muscular Dystrophy ◽

Ubiquitin Proteasome System ◽

Canine Model ◽

Ubiquitin Proteasome ◽

Myostatin Inhibition

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Long-Term Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy

Human Gene Therapy ◽

10.1089/hum.2011.102 ◽

2011 ◽

Vol 22 (12) ◽

pp. 1499-1509 ◽

Cited By ~ 33

Author(s):

Lawrence T. Bish ◽

Meg M. Sleeper ◽

Sean C. Forbes ◽

Kevin J. Morine ◽

Caryn Reynolds ◽

...

Keyword(s):

Muscular Dystrophy ◽

Gene Transfer ◽

Golden Retriever ◽

Golden Retriever Muscular Dystrophy ◽

Myostatin Inhibition

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The Failed Clinical Story of Myostatin Inhibitors Against Duchenne Muscular Dystrophy: Exploring the Biology Behind the Battle

10.20944/preprints202010.0234.v1 ◽

2020 ◽

Author(s):

Emma Rybalka ◽

Cara Timpani ◽

Danielle Debruin ◽

Ryan Bagaric ◽

Dean Campelj ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Clinical Data ◽

Muscle Wasting ◽

Disease Course ◽

Biological Mechanisms ◽

Outcomes Measures ◽

Myostatin Inhibition ◽

Secondary Outcomes ◽

Deficient Mice

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcomes measures selected: the myostatin inhibition story thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models has failed to translate into clinical benefit to patients has been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.

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Evaluation of Electrical Impedance as a Biomarker of Myostatin Inhibition in Wild Type and Muscular Dystrophy Mice

PLoS ONE ◽

10.1371/journal.pone.0140521 ◽

2015 ◽

Vol 10 (10) ◽

pp. e0140521 ◽

Cited By ~ 15

Author(s):

Benjamin Sanchez ◽

Jia Li ◽

Sung Yim ◽

Adam Pacheck ◽

Jeffrey J. Widrick ◽

...

Keyword(s):

Muscular Dystrophy ◽

Electrical Impedance ◽

Wild Type ◽

Myostatin Inhibition

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Electron Microscopy of Fibroblasts from Myotonic Muscular Dystrophy Patients

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100098976 ◽

1981 ◽

Vol 39 ◽

pp. 498-499

Author(s):

S. E. Miller ◽

G. B. Hartwig ◽

R. A. Nielsen ◽

A. P. Frost ◽

A. D. Roses

Keyword(s):

Electron Microscopy ◽

Muscular Dystrophy ◽

Genetic Diseases ◽

Skin Fibroblasts ◽

Inborn Errors ◽

Cytoplasmic Inclusions ◽

Cultured Skin ◽

Myotonic Muscular Dystrophy ◽

Glycosaminoglycan Metabolism

Many genetic diseases can be demonstrated in skin cells cultured in vitro from patients with inborn errors of metabolism. Since myotonic muscular dystrophy (MMD) affects many organs other than muscle, it seems likely that this defect also might be expressed in fibroblasts. Detection of an alteration in cultured skin fibroblasts from patients would provide a valuable tool in the study of the disease as it would present a readily accessible and controllable system for examination. Furthermore, fibroblast expression would allow diagnosis of fetal and presumptomatic cases. An unusual staining pattern of MMD cultured skin fibroblasts as seen by light microscopy, namely, an increase in alcianophilia and metachromasia, has been reported; both these techniques suggest an altered glycosaminoglycan metabolism An altered growth pattern has also been described. One reference on cultured skin fibroblasts from a different dystrophy (Duchenne Muscular Dystrophy) reports increased cytoplasmic inclusions seen by electron microscopy. Also, ultrastructural alterations have been reported in muscle and thalamus biopsies from MMD patients, but no electron microscopical data is available on MMD cultured skin fibroblasts.

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Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127943 ◽

1987 ◽

Vol 45 ◽

pp. 726-727

Author(s):

H. D. Geissinge ◽

L.D. Rhodes

Keyword(s):

Muscular Dystrophy ◽

Mouse Model ◽

Tibialis Anterior ◽

Physiological Activity ◽

Mdx Mice ◽

Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

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