Contractile properties, structure and fiber phenotype of intact and regenerating slow-twitch muscles of mice treated with cyclosporin A.
We have studied the contractile properties, structure, fiber-type composition, and myosin heavy chain (MyHC) expression pattern of regenerating and intact soleus muscles of adult CBA/J mice treated with cyclosporin A (CsA) or vehicle solutions (Cremophor, saline). A comparison of muscles after 4-7 weeks drug application with those receiving vehicle showed that the isometric contractile force of intact drug-treated muscles was reduced (tetanus, -21%; twitch, -34%) despite normal mass and muscle cross-sectional area. The frequency of fast-twitch fibers was increased, whereas no innervation deficits, histopathological alterations, or changes in fiber numbers were observed. Regeneration after cryolesion of the contralateral soleus proceeded more slowly in CsA-treated than in vehicle-treated animals. Despite this, when muscle properties reached mature levels (4-7 weeks), muscle mass recovery was better in CsA-treated animals (30% higher weight, 50% more fiber profiles in cross-sections). The force production per unit cross-sectional area was deficient, but not the maximum tension. Twitch time-to-peak and half-relaxation time were shorter than controls correlating with a predominance of fast-twitch fibers (98% Type II fibers versus 16%-18% in control muscles) and fast MyHC isoforms. Partial reversal of this fast phenotype and an increase in muscle force were observed when the animals were left to recover without treatment for 5-8 weeks after CsA application over 7 weeks. The high numbers of fiber profiles in CsA-treated regenerated muscles and increased mass remained unchanged after withdrawal. Thus, CsA treatment has a hyperplastic effect on regenerating muscles, and drug-induced phenotype alterations are much more prominent in regenerated muscles.
Irintchev
Andrey
A
Department of Physiology, Neurophysiology, University of Bonn, Wilhelmstrasse 31, 53111 Bonn, Germany. irintchev@physio.uni-bonn.de
Zweyer
Margit
M
Cooper
Racquel N
RN
Butler-Browne
Gillian S
GS
Wernig
Anton
A
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003285:Contractile Proteins / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D008808:Mice, Inbred CBA; D009119:Muscle Contraction / Q000187:drug effects*; D018657:Muscle Fibers, Slow-Twitch / Q000166:cytology* / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000378:metabolism; D010641:Phenotype; D012038:Regeneration / Q000187:drug effects
D003285:Contractile Proteins; D016572:Cyclosporine; D018995:Myosin Heavy Chains