Mice expressing L345P mutant desmin exhibit morphological and functional changes of skeletal and cardiac mitochondria.
Desmin mutations underlie inherited myopathies/cardiomyopathies with varying severity and involvement of the skeletal and cardiac muscles. We developed a transgenic mouse model expressing low level of the L345P desmin mutation (DESMUT mice) in order to uncover changes in skeletal and cardiac muscles caused by this mutation. The most striking ultrastructural changes in muscle from DESMUT mice were mitochondrial swelling and vacuolization. The mitochondrial Ca(2+) level was significantly increased in skeletal and cardiac myocytes from DESMUT mice compared to wild type cells during and after contractions. In isolated DESMUT soleus muscles, contractile function and recovery from fatigue were impaired. A SHIRPA screening test for neuromuscular performance demonstrated decreased motor function in DESMUT compared to WT mice. Echocardiographic changes in DESMUT mice included left ventricular wall hypertrophy and a decreased left ventricular chamber dimension. The results imply that low levels of L345P desmin acts, at least partially, by a dominant negative effect on mitochondria.
Kostareva
Anna
A
Department of Woman and Child Health and Center for Molecular Medicine, Karolinska Institute, L8:02, Stockholm 17176, Sweden.
Sjöberg
Gunnar
G
Bruton
Joseph
J
Zhang
Shi-Jin
SJ
Balogh
Johanna
J
Gudkova
Alexandra
A
Hedberg
Birgitta
B
Edström
Lars
L
Westerblad
Håkan
H
Sejersen
Thomas
T
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003893:Desmin / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D006321:Heart; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure*; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000648:ultrastructure*; D008933:Mitochondrial Swelling; D009119:Muscle Contraction; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000502:physiology; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure
D003893:Desmin; D002118:Calcium