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Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases
Published on: September 29, 2014
Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice
David M Thomson1, Chad R Hancock, Bradley G Evanson
1Department of Physiology and Developmental Biology, 589 WIDB, Brigham Young University, Provo, UT 84602, USA. david_thomson@byu.edu
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.
Insights
Liver kinase B1 (LKB1) is crucial for muscle health. LKB1 deficiency in mice causes severe muscle wasting, impaired movement, and heart failure, highlighting its vital role in maintaining skeletal and cardiac function.
Area of Science:
- Molecular Biology
- Physiology
- Genetics
Background:
- Liver kinase B1 (LKB1) is a tumor suppressor involved in regulating muscle metabolism and growth via AMP-activated protein kinase (AMPK) activation.
- LKB1's precise role in maintaining skeletal and cardiac muscle integrity is not fully understood.
Purpose of the Study:
- To investigate the physiological consequences of LKB1 deficiency specifically in skeletal and cardiac muscle.
- To elucidate the molecular mechanisms underlying LKB1-associated myopathy.
Main Methods:
- Development and analysis of skeletal and cardiac muscle-specific LKB1 knockout (mLKB1-KO) mice.
- Assessment of body weight, muscle mass, ambulation, and hindlimb function.
- Molecular analysis of key signaling pathways (mTOR, PGC-1α, CREB) and muscle fiber type composition.
Main Results:
- mLKB1-KO mice developed a myopathic phenotype by 30-50 weeks, characterized by reduced body and muscle weight, impaired ambulation, and hindlimb dysfunction.
- Skeletal muscle atrophy was linked to reduced mTOR pathway phosphorylation, lower PGC-1α and CREB levels, increased fatigue, and slowed relaxation.
- Cardiac abnormalities included dilated atria, suggesting heart failure, and decreased mitochondrial content and altered muscle fiber types in skeletal muscles.
Conclusions:
- LKB1 is essential for maintaining skeletal muscle mass, function, and metabolic homeostasis.
- LKB1 plays a critical role in preventing cardiac dysfunction and heart failure.
- These findings underscore LKB1's indispensable role in the overall maintenance of skeletal and cardiac health.
