Functional improvement of dystrophic muscle by myostatin blockade.
Mice and cattle with mutations in the myostatin (GDF8) gene show a marked increase in body weight and muscle mass, indicating that this new member of the TGF-beta superfamily is a negative regulator of skeletal muscle growth. Inhibition of the myostatin gene product is predicted to increase muscle mass and improve the disease phenotype in a variety of primary and secondary myopathies. We tested the ability of inhibition of myostatin in vivo to ameliorate the dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD). Blockade of endogenous myostatin by using intraperitoneal injections of blocking antibodies for three months resulted in an increase in body weight, muscle mass, muscle size and absolute muscle strength in mdx mouse muscle along with a significant decrease in muscle degeneration and concentrations of serum creatine kinase. The functional improvement of dystrophic muscle by myostatin blockade provides a novel, pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD, and circumvents the major problems associated with conventional gene therapy in these disorders.
Bogdanovich
Sasha
S
Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, 3700 Hamilton Walk, Richards A-601, Philadelphia, Pennsylvania 19104-6085, USA.
Krag
Thomas O B
TO
Barton
Elisabeth R
ER
Morris
Linda D
LD
Whittemore
Lisa-Anne
LA
Ahima
Rexford S
RS
Khurana
Tejvir S
TS
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D055435:Myostatin; D009929:Organ Size / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; C525912:Mstn protein, mouse; D055435:Myostatin; D016212:Transforming Growth Factor beta; D003402:Creatine Kinase; C506829:Stamulumab