The caveolin-cavin system plays a conserved and critical role in mechanoprotection of skeletal muscle.
Dysfunction of caveolae is involved in human muscle disease, although the underlying molecular mechanisms remain unclear. In this paper, we have functionally characterized mouse and zebrafish models of caveolae-associated muscle disease. Using electron tomography, we quantitatively defined the unique three-dimensional membrane architecture of the mature muscle surface. Caveolae occupied around 50% of the sarcolemmal area predominantly assembled into multilobed rosettes. These rosettes were preferentially disassembled in response to increased membrane tension. Caveola-deficient cavin-1(-/-) muscle fibers showed a striking loss of sarcolemmal organization, aberrant T-tubule structures, and increased sensitivity to membrane tension, which was rescued by muscle-specific Cavin-1 reexpression. In vivo imaging of live zebrafish embryos revealed that loss of muscle-specific Cavin-1 or expression of a dystrophy-associated Caveolin-3 mutant both led to sarcolemmal damage but only in response to vigorous muscle activity. Our findings define a conserved and critical role in mechanoprotection for the unique membrane architecture generated by the caveolin-cavin system.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Harriet P
HP
Lo
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Susan J
SJ
Nixon
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Thomas E
TE
Hall
Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de la Recherche Scientifique UMR7104, Strasbourg University, Illkirch 67404, France.
Belinda S
BS
Cowling
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia Center for Microscopy and Microanalysis, The University of Queensland, Brisbane, Queensland 4072, Australia.
Charles
C
Ferguson
Center for Microscopy and Microanalysis, The University of Queensland, Brisbane, Queensland 4072, Australia.
Garry P
GP
Morgan
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Nicole L
NL
Schieber
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Manuel A
MA
Fernandez-Rojo
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Michele
M
Bastiani
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia Center for Microscopy and Microanalysis, The University of Queensland, Brisbane, Queensland 4072, Australia.
Matthias
M
Floetenmeyer
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Nick
N
Martel
Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de la Recherche Scientifique UMR7104, Strasbourg University, Illkirch 67404, France.
Jocelyn
J
Laporte
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.
Paul F
PF
Pilch
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia Center for Microscopy and Microanalysis, The University of Queensland, Brisbane, Queensland 4072, Australia R.Parton@imb.uq.edu.au.
Robert G
RG
Parton
D000818:Animals; D022461:Caveolins / Q000235:genetics / Q000378:metabolism*; D055032:Electron Microscope Tomography; D040542:Mechanotransduction, Cellular; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D009136:Muscular Dystrophies / Q000235:genetics / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012508:Sarcolemma / Q000235:genetics / Q000473:pathology; D013314:Stress, Mechanical; D015027:Zebrafish
D022461:Caveolins; C112745:Cavin1 protein, mouse; D008565:Membrane Proteins; D016601:RNA-Binding Proteins