Functional muscle analysis of the Tcap knockout mouse

Hum Mol Genet. 2010 Jun 1;19(11):2268-83. doi: 10.1093/hmg/ddq105. Epub 2010 Mar 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Connectin
  • DNA Primers / genetics
  • Disease Models, Animal*
  • Electrophoresis, Polyacrylamide Gel
  • Gene Targeting / methods
  • Genetic Vectors / genetics
  • Immunoblotting
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Muscle Proteins / genetics*
  • Muscle Proteins / physiology
  • Muscle, Skeletal / physiopathology*
  • Muscle, Skeletal / ultrastructure
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Muscular Dystrophies, Limb-Girdle / physiopathology*
  • Myostatin / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Phenotype*
  • Rotarod Performance Test


  • Connectin
  • DNA Primers
  • Muscle Proteins
  • Myostatin
  • Tcap protein, mouse