Enhancing muscle membrane repair by gene delivery of MG53 ameliorates muscular dystrophy and heart failure in δ-Sarcoglycan-deficient hamsters.
Muscular dystrophies (MDs) are caused by genetic mutations in over 30 different genes, many of which encode for proteins essential for the integrity of muscle cell structure and membrane. Their deficiencies cause the muscle vulnerable to mechanical and biochemical damages, leading to membrane leakage, dystrophic pathology, and eventual loss of muscle cells. Recent studies report that MG53, a muscle-specific TRIM-family protein, plays an essential role in sarcolemmal membrane repair. Here, we show that systemic delivery and muscle-specific overexpression of human MG53 gene by recombinant adeno-associated virus (AAV) vectors enhanced membrane repair, ameliorated pathology, and improved muscle and heart functions in δ-sarcoglycan (δ-SG)-deficient TO-2 hamsters, an animal model of MD and congestive heart failure. In addition, MG53 overexpression increased dysferlin level and facilitated its trafficking to muscle membrane through participation of caveolin-3. MG53 also protected muscle cells by activating cell survival kinases, such as Akt, extracellular signal-regulated kinases (ERK1/2), and glycogen synthase kinase-3β (GSK-3β) and inhibiting proapoptotic protein Bax. Our results suggest that enhancing the muscle membrane repair machinery could be a novel therapeutic approach for MD and cardiomyopathy, as demonstrated here in the limb girdle MD (LGMD) 2F model.
Division of Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
Bo
B
He
Ru-hang
RH
Tang
Noah
N
Weisleder
Bin
B
Xiao
Zhenhua
Z
Yuan
Chuanxi
C
Cai
Hua
H
Zhu
Peihui
P
Lin
Chunping
C
Qiao
Jianbin
J
Li
Christina
C
Mayer
Juan
J
Li
Jianjie
J
Ma
Xiao
X
Xiao
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009136:Muscular Dystrophies / Q000378:metabolism / Q000628:therapy*; D049031:Sarcoglycans / Q000172:deficiency*; D000070584:Tripartite Motif Proteins
D002352:Carrier Proteins; D051244:Caveolin 3; D009124:Muscle Proteins; D049031:Sarcoglycans; C558399:TRIM72 protein, human; D000070584:Tripartite Motif Proteins