The inﬂuence of muscle type and dystrophin deﬁciency on murine
Judith N. Haslett,
* Peter B. Kang,
* Mei Han,
Alvin T. Kho,
Jay M. Volinski,
Alan H. Beggs,
Isaac S. Kohane,
Louis M. Kunkel
Division of Genetics and Genomics Program, ChildrenÕs Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115,
Department of Neurology, ChildrenÕs Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA
Informatics Program, ChildrenÕs Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA
Division of Endocrinology, ChildrenÕs Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA
Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA
Received: 6 April 2005 / Accepted: 16 June 2005
The phenotypic differences among Duchenne mus-
cular dystrophy patients, mdx mice, and mdx
mice suggest that despite the common etiology of
dystrophin deficiency, secondary mechanisms have
a substantial influence on phenotypic severity. The
differential response of various skeletal muscles to
dystrophin deficiency supports this hypothesis. To
explore these differences, gene expression profiles
were generated from duplicate RNA targets ex-
tracted from six different skeletal muscles (dia-
phragm, soleus, gastrocnemius, quadriceps, tibialis
anterior, and extensor digitorum longus) from wild-
mice, resulting in 36 data sets
for 18 muscle samples. The data sets were compared
in three different ways: (1) among wild-type samples
only, (2) among all 36 data sets, and (3) between
strains for each muscle type. The molecular profiles
of soleus and diaphragm separate significantly from
the other four muscle types and from each other.
Fiber-type proportions can explain some of these
differences. These variations in wild-type gene
expression profiles may also reflect biomechanical
differences known to exist among skeletal muscles.
Further exploration of the genes that most
distinguish these muscles may help explain the ori-
gins of the biomechanical differences and the rea-
sons why some muscles are more resistant than
others to dystrophin deficiency.
The primary defect in Duchenne muscular dystro-
phy (DMD) and its mouse models, including the
mdx and mdx
strains, is the absence of dystrophin
(Hoffman et al. 1987), an essential member of the
dystrophin-associated protein complex that spans
the sarcolemma of skeletal muscle fibers (Ervasti
et al. 1990; Ervasti and Campbell 1991; Koenig et al.
1988; Yoshida et al. 1990).
The mdx mouse has a naturally occurring non-
sense mutation in exon 23 of dystrophin (Bulfield
et al. 1984; Ryder-Cook et al. 1988; Sicinski et al.
1989) and a significantly milder phenotype than
DMD (Durbeej et al. 2002; Hoffman et al. 1987;
Sicinski et al. 1989). Mdx hindlimb muscles exhibit
intense necrosis and regeneration between two and
six weeks of age, followed by stabilization, accom-
panied by hypertrophy and dystrophic degeneration
in older mice (Hoffman and Gorospe 1991; McArdle
et al. 1994). In contrast, mdx diaphragm undergoes
extensive degeneration similar to the phenotype of
DMD patients (Stedman et al. 1991).
The ethylnitrosourea-induced mdx
a mutation in exon 10 of dystrophin that creates a
novel splice site, inducing aberrant splicing and an
absence of dystrophin (Chapman et al. 1989). The
phenotype is also milder than that of DMD.
mice have ten times fewer revert-
ant (dystrophin-positive) fibers than mdx mice and
are slightly more severely affected (Danko et al.
*These authors contributed equally to this work.
Correspondence to: Louis M. Kunkel, Genomics Program, Enders
570, Children’s Hospital Boston, 300 Longwood Avenue, Boston,
MA 02115, USA; E-mail: email@example.com
DOI: 10.1007/s00335-005-0053-8 Volume 16, 739À748 (2005) Ó Springer Science+Business Media, Inc. 2005