Journal Article

Functional muscle analysis of the Tcap knockout mouse

C.D. Markert, M.P. Meaney, K.A. Voelker, R.W. Grange, H.W. Dalley, J.K. Cann, M. Ahmed, B. Bishwokarma, S.J. Walker, S.X. Yu, M. Brown, M.W. Lawlor, A.H. Beggs and M.K. Childers

in Human Molecular Genetics

Volume 19, issue 11, pages 2268-2283
Published in print June 2010 | ISSN: 0964-6906
Published online March 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq105
Functional muscle analysis of the Tcap knockout mouse

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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.

Journal Article.  8933 words.  Illustrated.

Subjects: Genetics and Genomics

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