Myostatin blockade improves function but not histopathology in a murine model of limb-girdle muscular dystrophy 2C.
Myostatin is a negative regulator of skeletal muscle growth. Myostatin mutations and pharmacological strategies increase muscle mass in vivo, suggesting that myostatin blockade may prove useful in diseases characterized by muscle wasting, such as the muscular dystrophies. We subjected the gamma-sarcoglycan-deficient (Sgcg(-/-)) mouse model of limb-girdle muscular dystrophy (LGMD) 2C to antibody-mediated myostatin blockade in vivo. Myostatin inhibition led to increased fiber size, muscle mass, and absolute force. However, no clear improvement in muscle histopathology was evident, demonstrating discordance between physiological and histological improvement. These results and previous studies on the dyw/dyw mouse model of congenital muscular dystrophy and in the late-stage delta-sarcoglycan-deficient (Sgcd(-/-)) mouse model of LGMD2F document disease-specific limitations to therapeutic strategies based on myostatin blockade in the more severe mouse models of different muscular dystrophies.
Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, 3700 Hamilton Walk, Philadelphia, PA 19104-6085, USA.
Sasha
S
Bogdanovich
Elizabeth M
EM
McNally
Tejvir S
TS
Khurana
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D055435:Myostatin; D045442:Rotarod Performance Test / Q000379:methods; D049031:Sarcoglycans / Q000172:deficiency; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism*
D000906:Antibodies; C525912:Mstn protein, mouse; D055435:Myostatin; D049031:Sarcoglycans; D016212:Transforming Growth Factor beta; D003402:Creatine Kinase; D053148:Caspase 3