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.
Markert
C D
CD
Department of Neurology, Wake Forest University, Winston-Salem, NC 27101, USA.
Meaney
M P
MP
Voelker
K A
KA
Grange
R W
RW
Dalley
H W
HW
Cann
J K
JK
Ahmed
M
M
Bishwokarma
B
B
Walker
S J
SJ
Yu
S X
SX
Brown
M
M
Lawlor
M W
MW
Beggs
A H
AH
Childers
M K
MK
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