Myotendinous junction defects and reduced force transmission in mice that lack alpha7 integrin and utrophin.
The alpha7beta1 integrin, dystrophin, and utrophin glycoprotein complexes are the major laminin receptors in skeletal muscle. Loss of dystrophin causes Duchenne muscular dystrophy, a lethal muscle wasting disease. Duchenne muscular dystrophy-affected muscle exhibits increased expression of alpha7beta1 integrin and utrophin, which suggests that these laminin binding complexes may act as surrogates in the absence of dystrophin. Indeed, mice that lack dystrophin and alpha7 integrin (mdx/alpha7(-/-)), or dystrophin and utrophin (mdx/utr(-/-)), exhibit severe muscle pathology and die prematurely. To explore the contribution of the alpha7beta1 integrin and utrophin to muscle integrity and function, we generated mice lacking both alpha7 integrin and utrophin. Surprisingly, mice that lack both alpha7 integrin and utrophin (alpha7/utr(-/-)) were viable and fertile. However, these mice had partial embryonic lethality and mild muscle pathology, similar to alpha7 integrin-deficient mice. Dystrophin levels were increased 1.4-fold in alpha7/utr(-/-) skeletal muscle and were enriched at neuromuscular junctions. Ultrastructural analysis revealed abnormal myotendinous junctions, and functional tests showed a ninefold reduction in endurance and 1.6-fold decrease in muscle strength in these mice. The alpha7/utr(-/-) mouse, therefore, demonstrates the critical roles of alpha7 integrin and utrophin in maintaining myotendinous junction structure and enabling force transmission during muscle contraction. Together, these results indicate that the alpha7beta1 integrin, dystrophin, and utrophin complexes act in a concerted manner to maintain the structural and functional integrity of skeletal muscle.
Welser
Jennifer V
JV
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Rooney
Jachinta E
JE
Cohen
Nicolette C
NC
Gurpur
Praveen B
PB
Singer
Cherie A
CA
Evans
Rebecca A
RA
Haines
Bryan A
BA
Burkin
Dean J
DJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001696:Biomechanical Phenomena; D003433:Crosses, Genetic; D016189:Dystrophin / Q000378:metabolism; D020964:Embryo Loss / Q000473:pathology; D005260:Female; D005298:Fertility; D040582:Inheritance Patterns / Q000235:genetics; D039001:Integrin alpha Chains / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053580:Muscle Strength / Q000502:physiology; D009132:Muscles / Q000473:pathology* / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000378:metabolism; D010641:Phenotype; D017474:Receptors, Laminin / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism / Q000473:pathology; D013710:Tendons / Q000473:pathology*; D049411:Utrophin / Q000172:deficiency* / Q000378:metabolism; D015430:Weight Gain
D015703:Antigens, CD; D016189:Dystrophin; D039001:Integrin alpha Chains; D017474:Receptors, Laminin; D049411:Utrophin; C085725:integrin alpha7