Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy

Stephanie A. Parsons, Douglas P. Millay, Michelle A. Sargent, Elizabeth M. McNally, Jeffery D. Molkentin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Myostatin (MSTN) is a muscle-specific secreted peptide that functions to limit muscle growth through an autocrine regulatory feedback loop. Loss of MSTN activity in cattle, mice, and humans leads to a profound phenotype of muscle overgrowth, associated with more and larger fibers and enhanced regenerative capacity. Deletion of MSTN in the mdx mouse model of Duchenne muscular dystrophy enhances muscle mass and reduces disease severity. In contrast, loss of MSTN activity in the dyW/dyw mouse model of lamtain-deflcient congenital muscular dystrophy, a much more severe and lethal disease model, does not improve all aspects of muscle pathology. Here we examined disease severity associated with myostatin (mstn-/-) deletion in mice nulizygows for δ-sarcogfycan (scgd-/-), a model of limb-girdle muscular dystrophy. Early loss of MSTN activity achieved either by monoclonal antibody administration or by gene deletion each improved muscle mass, regeneration, and reduced fibrosis in scgd-/- mice. However, antibody-mediated inhibition of MSTN in latestage dystrophic scgd-/- mice did not improve disease. These findings suggest that MSTN inhibition may benefit muscular dystrophy when instituted early or if disease is relatively mild but that MSTN inhibition hi severely affected or late-stage disease may be ineffective.

Original languageEnglish (US)
Pages (from-to)1975-1985
Number of pages11
JournalAmerican Journal of Pathology
Volume168
Issue number6
DOIs
StatePublished - Jun 2006

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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