Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice

Department of Physiology and Developmental Biology, 589 WIDB, Brigham Young University, Provo, UT 84602, USA.
Journal of Applied Physiology (Impact Factor: 3.43). 04/2010; 108(6):1775-85. DOI: 10.1152/japplphysiol.01293.2009
Source: PubMed

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.

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    • "Given the increased fatigability of KO diaphragms that we show here, and the previously reported finding that voluntary wheel running distance is lower in KO mice, it might be surmised that the apparent shift to IIb MHC is due to decreased overall activity of the KO mice. However, ambulatory activity in young female (Thomson et al., 2010) and male (unpublished results from our laboratory) KO mice is not different than that of C mice. Therefore, the alteration in fiber-type and mitochondrial protein content does not appear to be due to decreased physical activity, assuming that respiratory activity tracks well with ambulation in these mice. "
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