Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy. Proc Natl Acad Sci U S A 2003 Jul 22;100(15):8910-5
Date
07/10/2003Pubmed ID
12851463Pubmed Central ID
PMC166412DOI
10.1073/pnas.1537554100Scopus ID
2-s2.0-0041806537 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
Limb-girdle muscular dystrophy types 2E and F are characterized by skeletal muscle weakness and often cardiomyopathy and are due to mutations in the genes encoding beta- and delta-sarcoglycan. We previously demonstrated that loss of sarcoglycans in smooth muscle leads to constrictions of the microvasculature that contributes to the cardiac phenotype. It is unclear how vasculature abnormalities affect skeletal muscle. We injected recombinant beta- or delta-sarcoglycan adenoviruses into skeletal muscles of corresponding null mice. We hypothesized that the adenoviruses would not transduce vascular smooth muscle, and we would only target skeletal muscle. Indeed, sustained expression of intact sarcoglycan-sarcospan complex was noted at the sarcolemma, neuromuscular junction, myotendinous junction, and in peripheral nerve, but not in vascular smooth muscle. Gene transfer of the corresponding deleted sarcoglycan gene preserved sarcolemmal integrity, prevented pathological dystrophy and hypertrophy, and protected against exercised-induced damage. We conclude that vascular dysfunction is not a primary cause of beta- and delta-sarcoglycan-deficient muscular dystrophy. In addition, we show successful functional rescue of entire muscles after adenovirus-mediated gene delivery. Thus, virus-mediated gene transfer of sarcoglycans to skeletal muscle in combination with pharmacological prevention of cardiomyopathy constitute promising therapeutic strategies for limb-girdle muscular dystrophies.
Author List
Durbeej M, Sawatzki SM, Barresi R, Schmainda KM, Allamand V, Michele DE, Campbell KPAuthor
Kathleen M. Schmainda PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenoviridaeAnimals
Cytoskeletal Proteins
Dystroglycans
Gene Transfer Techniques
Genetic Therapy
Macromolecular Substances
Membrane Glycoproteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal
Muscle, Smooth
Muscle, Smooth, Vascular
Muscular Dystrophies
Muscular Dystrophy, Animal
Neuromuscular Junction
Physical Exertion
Sarcoglycans
Sarcolemma
Schwann Cells
