Caveolin-1(-/-)- and caveolin-2(-/-)-deficient mice both display numerous skeletal muscle abnormalities, with tubular aggregate formation.
Here, we examine the role of "non-muscle" caveolins (Cav-1 and Cav-2) in skeletal muscle biology. Our results indicate that skeletal muscle fibers from male Cav-1(-/-) and Cav-2(-/-) mice show striking abnormalities, such as tubular aggregates, mitochondrial proliferation/aggregation, and increased numbers of M-cadherin-positive satellite cells. Notably, these skeletal muscle defects were more pronounced with increasing age. Because Cav-2-deficient mice displayed normal expression levels of Cav-1, whereas Cav-1-null mice exhibited an almost complete deficiency in Cav-2, these skeletal muscle abnormalities seem to be due to loss of Cav-2. Thus, Cav-2(-/-) mice represent a novel animal model-and the first genetically well-defined mouse model-that can be used to study the pathogenesis of tubular aggregate formation, which remains a poorly understood age-related skeletal muscle abnormality. Finally, because Cav-1 and Cav-2 were not expressed within mature skeletal myofibers, our results indicate that development of these abnormalities probably originates in stem/precursor cells, such as satellite cells or myoblasts. Consistent with this hypothesis, skeletal muscle isolated from male Cav-3(-/-) mice did not show any of these abnormalities. As such, this is the first study linking stem cells with the genesis of these intriguing muscle defects.
Schubert
William
W
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA.
Sotgia
Federica
F
Cohen
Alex W
AW
Capozza
Franco
F
Bonuccelli
Gloria
G
Bruno
Claudio
C
Minetti
Carlo
C
Bonilla
Eduardo
E
Dimauro
Salvatore
S
Lisanti
Michael P
MP
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics*; D051243:Caveolin 2 / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000032:analysis; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000378:metabolism / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology
D015820:Cadherins; D051242:Caveolin 1; D051243:Caveolin 2; C070896:M-cadherin; D003576:Electron Transport Complex IV