Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice

• Published in: Journal of applied physiology (1985) Vol. 108; no. 6; pp. 1775 - 1785
• Main Authors: THOMSON, David M, HANCOCK, Chad R, KOOYMAN, David L, WINDER, William W, EVANSON, Bradley G, KENNEY, Steven G, MALAN, Brandon B, MONGILLO, Anthony D, BROWN, Jacob D, HEPWORTH, Squire, FILLMORE, Natasha, PARCELL, Allen C
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Physiological Society 01.06.2010
• Subjects: Animals; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Kinases; Mice; Mice, Knockout; Muscle Fatigue; Muscle, Skeletal - physiopathology; Muscular Diseases - physiopathology; Musculoskeletal system; Phosphorylation; Physiology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Rodents; Purine nucleoside; Sirolimus; Non-specific serine/threonine protein kinase; Macrocycle; Binding protein; Mitochondria; mammalian target of rapamycin; Protein synthesis inhibitor; Adenosine; Enzyme; Transferases; Rodentia; Lactone; Striated muscle; Macrolide; Response element; adenosine 5'-monophosphate-activated protein kinase; Vertebrata; Mammalia; Mouse; Dysfunction; adenosine 3',5'-cyclic monophosphate response element binding protein; Mutation; cardiac myopathy; Myopathy
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.01293.2009

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.