Cytoplasmic gamma-actin is not required for skeletal muscle development but its absence leads to a progressive myopathy.
Nonmuscle gamma(cyto)-actin is expressed at very low levels in skeletal muscle but uniquely localizes to costameres, the cytoskeletal networks that couple peripheral myofibrils to the sarcolemma. We generated and analyzed skeletal muscle-specific gamma(cyto)-actin knockout (Actg1-msKO) mice. Although muscle development proceeded normally, Actg1-msKO mice presented with overt muscle weakness accompanied by a progressive pattern of muscle fiber necrosis/regeneration. Functional deficits in whole-body tension and isometric twitch force were observed, consistent with defects in the connectivity between muscle fibers and/or myofibrils or at the myotendinous junctions. Surprisingly, gamma(cyto)-actin-deficient muscle did not demonstrate the fibrosis, inflammation, and membrane damage typical of several muscular dystrophies but rather presented with a novel progressive myopathy. Together, our data demonstrate an important role for minimally abundant but strategically localized gamma(cyto)-actin in adult skeletal muscle and describe a new mouse model to study the in vivo relevance of subcellular actin isoform sorting.
Sonnemann
Kevin J
KJ
Program in Cellular and Molecular Biology, University of Wisconsin-Madison, 53706, USA.
Fitzsimons
Daniel P
DP
Patel
Jitandrakumar R
JR
Liu
Yewei
Y
Schneider
Martin F
MF
Moss
Richard L
RL
Ervasti
James M
JM
D000199:Actins / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000196:embryology* / Q000378:metabolism; D009135:Muscular Diseases / Q000378:metabolism* / Q000473:pathology; D038081:Organogenesis
D000199:Actins; D016189:Dystrophin; D006023:Glycoproteins