Functional muscle analysis of the Tcap knockout mouse.
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.
Department of Neurology, Wake Forest University, Winston-Salem, NC 27101, USA.
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Markert
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Meaney
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Voelker
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Grange
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Dalley
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Cann
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Ahmed
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Bishwokarma
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Walker
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Yu
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Brown
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Lawlor
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Beggs
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Childers
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D064211:Connectin; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D018390:Gene Targeting / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology; D018482:Muscle, Skeletal / Q000503:physiopathology* / Q000648:ultrastructure; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000503:physiopathology*; D055435:Myostatin / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D045442:Rotarod Performance Test
D064211:Connectin; D017931:DNA Primers; D009124:Muscle Proteins; D055435:Myostatin; C577294:Tcap protein, mouse