TY - JOUR
T1 - Stimulation of calcineurin Aα activity attenuates muscle pathophysiology in mdx dystrophic mice
AU - Stupka, Nicole
AU - Schertzer, Jonathan D.
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
AU - Lynch, Gordon S.
PY - 2008/3/1
Y1 - 2008/3/1
N2 - Calcineurin activation ameliorates the dystrophic pathology of hindlimb muscles in mdx mice and decreases their susceptibility to contraction damage. In mdx mice, the diaphragm is more severely affected than hindlimb muscles and more representative of Duchenne muscular dystrophy. The constitutively active calcineurin Aα transgene (CnAα) was overexpressed in skeletal muscles of mdx (mdx CnAα*) mice to test whether muscle morphology and function would be improved. Contractile function of diaphragm strips and extensor digitorum longus and soleus muscles from adult mdx CnAα* and mdx mice was examined in vitro. Hindlimb muscles from mdx CnAα* mice had a prolonged twitch time course and were more resistant to fatigue. Because of a slower phenotype and a decrease in fiber cross-sectional area, normalized force was lower in fast- and slow-twitch muscles of mdx CnAα* than mdx mice. In the diaphragm, despite a slower phenotype and a ∼35% reduction in fiber size, normalized force was preserved. This was likely mediated by the reduction in the area of the diaphragm undergoing degeneration (i.e., mononuclear cell and connective and adipose tissue infiltration). The proportion of centrally nucleated fibers was reduced in mdx CnAα* compared with mdx mice, indicative of improved myofiber viability. In hindlimb muscles of mdx mice, calcineurin activation increased expression of markers of regeneration, particularly developmental myosin heavy chain isoform and myocyte enhancer factor 2A. Thus activation of the calcineurin signal transduction pathway has potential to ameliorate the mdx pathophysiology, especially in the diaphragm, through its effects on muscle degeneration and regeneration and endurance capacity.
AB - Calcineurin activation ameliorates the dystrophic pathology of hindlimb muscles in mdx mice and decreases their susceptibility to contraction damage. In mdx mice, the diaphragm is more severely affected than hindlimb muscles and more representative of Duchenne muscular dystrophy. The constitutively active calcineurin Aα transgene (CnAα) was overexpressed in skeletal muscles of mdx (mdx CnAα*) mice to test whether muscle morphology and function would be improved. Contractile function of diaphragm strips and extensor digitorum longus and soleus muscles from adult mdx CnAα* and mdx mice was examined in vitro. Hindlimb muscles from mdx CnAα* mice had a prolonged twitch time course and were more resistant to fatigue. Because of a slower phenotype and a decrease in fiber cross-sectional area, normalized force was lower in fast- and slow-twitch muscles of mdx CnAα* than mdx mice. In the diaphragm, despite a slower phenotype and a ∼35% reduction in fiber size, normalized force was preserved. This was likely mediated by the reduction in the area of the diaphragm undergoing degeneration (i.e., mononuclear cell and connective and adipose tissue infiltration). The proportion of centrally nucleated fibers was reduced in mdx CnAα* compared with mdx mice, indicative of improved myofiber viability. In hindlimb muscles of mdx mice, calcineurin activation increased expression of markers of regeneration, particularly developmental myosin heavy chain isoform and myocyte enhancer factor 2A. Thus activation of the calcineurin signal transduction pathway has potential to ameliorate the mdx pathophysiology, especially in the diaphragm, through its effects on muscle degeneration and regeneration and endurance capacity.
KW - Muscle contraction
KW - Muscle regeneration
KW - Muscular dystrophy
KW - Skeletal muscle
UR - http://www.scopus.com/inward/record.url?scp=40449139951&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40449139951&partnerID=8YFLogxK
U2 - 10.1152/ajpregu.00375.2007
DO - 10.1152/ajpregu.00375.2007
M3 - Article
C2 - 18199592
AN - SCOPUS:40449139951
SN - 0363-6119
VL - 294
SP - R983-R992
JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
IS - 3
ER -