Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice.
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.
Thomson
David M
DM
Department of Physiology and Developmental Biology, 589 WIDB, Brigham Young University, Provo, UT 84602, USA. david_thomson@byu.edu
Hancock
Chad R
CR
Evanson
Bradley G
BG
Kenney
Steven G
SG
Malan
Brandon B
BB
Mongillo
Anthony D
AD
Brown
Jacob D
JD
Hepworth
Squire
S
Fillmore
Natasha
N
Parcell
Allen C
AC
Kooyman
David L
DL
Winder
William W
WW
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*
D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases