Functional muscle analysis of the Tcap knockout mouse. Hum Mol Genet 2010 Jun 01;19(11):2268-83
Date
03/18/2010Pubmed ID
20233748Pubmed Central ID
PMC2865379DOI
10.1093/hmg/ddq105Scopus ID
2-s2.0-77953511024 (requires institutional sign-in at Scopus site) 43 CitationsAbstract
Autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G) is an adult-onset myopathy characterized by distal lower limb weakness, calf hypertrophy and progressive decline in ambulation. The disease is caused by mutations in Tcap, a z-disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout (KO) mice carrying a null mutation in the Tcap gene. Here we present the first report of a Tcap KO mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4- and 12-month-old mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of Tcap was accompanied by increased protein levels of myostatin. Our Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild-type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus (SOL) muscles. Finally, a mechanical investigation of EDL and SOL indicated an increase in muscle stiffness in KO animals. We are the first to establish a viable KO mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.
Author List
Markert CD, Meaney MP, Voelker KA, Grange RW, Dalley HW, Cann JK, Ahmed M, Bishwokarma B, Walker SJ, Yu SX, Brown M, Lawlor MW, Beggs AH, Childers MKAuthor
Michael W. Lawlor PhD, MD Adjunct Professor in the Pathology and Laboratory Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Age FactorsAnalysis of Variance
Animals
Connectin
DNA Primers
Disease Models, Animal
Electrophoresis, Polyacrylamide Gel
Gene Targeting
Genetic Vectors
Immunoblotting
Mice
Mice, Knockout
Microscopy, Electron
Muscle Proteins
Muscle, Skeletal
Muscular Dystrophies, Limb-Girdle
Myostatin
Oligonucleotide Array Sequence Analysis
Phenotype
Rotarod Performance Test
