title: Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice.
abstract: Liver kinase B1 (LKB1) is a tumor-suppressing protein that is involved in the regulation of muscle metabolism and growth by phosphorylating and activating AMP-activated protein kinase (AMPK) family members. Here we report the development of a myopathic phenotype in skeletal and cardiac muscle-specific LKB1 knockout (mLKB1-KO) mice. The myopathic phenotype becomes overtly apparent at 30-50 wk of age and is characterized by decreased body weight and a proportional reduction in fast-twitch skeletal muscle weight. The ability to ambulate is compromised with an often complete loss of hindlimb function. Skeletal muscle atrophy is associated with a 50-75% reduction in mammalian target of rapamycin pathway phosphorylation, as well as lower peroxisome proliferator-activated receptor-alpha coactivator-1 content and cAMP response element binding protein phosphorylation (43 and 40% lower in mLKB1-KO mice, respectively). Maximum in situ specific force production is not affected, but fatigue is exaggerated, and relaxation kinetics are slowed in the myopathic mice. The increased fatigue is associated with a 30-78% decrease in mitochondrial protein content, a shift away from type IIA/D toward type IIB muscle fibers, and a tendency (P=0.07) for decreased capillarity in mLKB1-KO muscles. Hearts from myopathic mLKB1-KO mice exhibit grossly dilated atria, suggesting cardiac insufficiency and heart failure, which likely contributes to the phenotype. These findings indicate that LKB1 plays a critical role in the maintenance of both skeletal and cardiac function.
authors.affiliation: Department of Physiology and Developmental Biology, 589 WIDB, Brigham Young University, Provo, UT 84602, USA. david_thomson@byu.edu
authors.forename: David M
authors.initials: DM
authors.lastname: Thomson
authors.forename: Chad R
authors.initials: CR
authors.lastname: Hancock
authors.forename: Bradley G
authors.initials: BG
authors.lastname: Evanson
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kenney
authors.forename: Brandon B
authors.initials: BB
authors.lastname: Malan
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Mongillo
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Brown
authors.forename: Squire
authors.initials: S
authors.lastname: Hepworth
authors.forename: Natasha
authors.initials: N
authors.lastname: Fillmore
authors.forename: Allen C
authors.initials: AC
authors.lastname: Parcell
authors.forename: David L
authors.initials: DL
authors.lastname: Kooyman
authors.forename: William W
authors.initials: WW
authors.lastname: Winder
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D018763:Muscle Fatigue; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009135:Muscular Diseases / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases