Myofiber damage precedes macrophage infiltration after in vivo injury in dysferlin-deficient A/J mouse skeletal muscle.
Mutations in the dysferlin gene (DYSF) lead to human muscular dystrophies known as dysferlinopathies. The dysferlin-deficient A/J mouse develops a mild myopathy after 6 months of age, and when younger models the subclinical phase of the human disease. We subjected the tibialis anterior muscle of 3- to 4-month-old A/J mice to in vivo large-strain injury (LSI) from lengthening contractions and studied the progression of torque loss, myofiber damage, and inflammation afterward. We report that myofiber damage in A/J mice occurs before inflammatory cell infiltration. Peak edema and inflammation, monitored by magnetic resonance imaging and by immunofluorescence labeling of neutrophils and macrophages, respectively, develop 24 to 72 hours after LSI, well after the appearance of damaged myofibers. Cytokine profiles 72 hours after injury are consistent with extensive macrophage infiltration. Dysferlin-sufficient A/WySnJ mice show much less myofiber damage and inflammation and lesser cytokine levels after LSI than do A/J mice. Partial suppression of macrophage infiltration by systemic administration of clodronate-incorporated liposomes fails to suppress LSI-induced damage or to accelerate torque recovery in A/J mice. The findings from our studies suggest that, although macrophage infiltration is prominent in dysferlin-deficient A/J muscle after LSI, it is the consequence and not the cause of progressive myofiber damage.
Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland. Electronic address: joseph.roche@wayne.edu.
Joseph A
JA
Roche
Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland.
Mohan E
ME
Tulapurkar
Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland.
Amber L
AL
Mueller
Clodronateliposomes.com, Amsterdam, the Netherlands; Department of Molecular Cell Biology, Faculty of Medicine, VU University Medical Center, Amsterdam, the Netherlands.
Nico
N
van Rooijen
Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland.
Jeffrey D
JD
Hasday
Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, Maryland.
Richard M
RM
Lovering
Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland.
Robert J
RJ
Bloch
D000818:Animals; D004195:Disease Models, Animal; D000073939:Dysferlin; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism / Q000473:pathology*
C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins