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Targeted expression of the non‐native Ca +2 ‐buffering protein parvalbumin exacerbates the dystrophic phenotype in mdx mouse slow muscle fibers
Author(s) -
Zein Manal Al,
Chin Eva R.,
Jasmin Bernard J.,
Michel Robin N.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1086.23
Subject(s) - utrophin , dystrophin , parvalbumin , mdx mouse , duchenne muscular dystrophy , microbiology and biotechnology , muscular dystrophy , skeletal muscle , soleus muscle , chemistry , myocyte , myosin , phenotype , transgene , medicine , biology , endocrinology , biochemistry , neuroscience , gene
We set out to determine the impact of interfering with Ca +2 /CaMbased signaling in dystrophin‐deficient myofibers. We thus crossbred mdx mice with transgenic mice expressing the Ca +2 ‐ buffering protein parvalbumin (PV), driven by the fiber‐specific Troponin I slow promoter. This approach forced expression of this non‐native fast Ca +2 ‐regulatory protein in slow fibers. Consistent with impairments in the downstream Ca +2 /CaM‐regulated enzyme calcineurin (Cn), the nuclear localization of NFATc1 was reduced in fibers from mdx/PV mice. We also detected significant reductions in Cn activity in slow fiber‐rich soleus muscles of mdx/PV mice in the absence of any fiber type conversions. Examination of mdx/PV muscle fibers revealed significant reductions in utrophin A, a therapeutically relevant protein that can compensate for the lack of dystrophin in skeletal muscle. In accordance with lower levels of utrophin A, we noted a clear exacerbation of the dystrophic phenotype in mdx/PV slow fibers as exemplified by several pathological indices such as increased fiber size variability and number of centrally located nuclei. These results further establish Ca +2 /CaM‐based signaling as key to regulating expression of utrophin A in muscle. Moreover, they illustrate the therapeutic potential of targeting Ca +2 /CaM‐ based signaling intermediates as well as strategies aimed at promoting the slow oxidative myofiber program in muscle, as effective countermeasures for Duchenne muscular dystrophy.