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.
We recently reported a novel form of BMP2, designated nBMP2, which is translated from an alternative downstream start codon and is localized to the nucleus rather than secreted from the cell. To examine the function of nBMP2 in the nucleus, we engineered a gene-targeted mutant mouse model (nBmp2NLStm) in which nBMP2 cannot be translocated to the nucleus. Immunohistochemistry demonstrated the presence of nBMP2 staining in the myonuclei of wild type but not mutant skeletal muscle. The nBmp2NLStm mouse exhibits altered function of skeletal muscle as demonstrated by a significant increase in the time required for relaxation following a stimulated twitch contraction. Force frequency analysis showed elevated force production in mutant muscles compared to controls from 10 to 60 Hz stimulation frequency, consistent with the mutant muscle's reduced ability to relax between rapidly stimulated contractions. Muscle relaxation after contraction is mediated by the active transport of Ca2+ from the cytoplasm to the sarcoplasmic reticulum by sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and enzyme activity assays revealed that SERCA activity in skeletal muscle from nBmp2NLStm mice was reduced to approximately 80% of wild type. These results suggest that nBMP2 plays a role in the establishment or maintenance of intracellular Ca2+ transport pathways in skeletal muscle.
Conventional bone morphogenetic protein 2 (Bmp2) is a secreted growth factor characterized by its ability to induce bone and cartilage formation, and by its role in developmental processes such as axis formation, cardiac development, and neuronal differentiation. Recently, however, we have identified a novel form of Bmp2 (nBmp2) that is translated from an alternative start codon and is localized to the nucleus rather than being secreted. To study the function of nBmp2 in the nucleus, we generated mice bearing an nBmp2 mutation that prevents nuclear localization. Here we evaluate muscle performance in these mutant mice using in situ stimulation of the gastrocnemius, plantaris, soleus (GPS) muscle complex via the sciatic nerve. Specific peak tetanic force of the GPS muscle group was slightly higher in nBmp2 deficient mice compared to control mice (3.3 ± 0.1 and 3.1 ± 0.1 gm tension/mg muscle in mutant vs. control muscles, respectively, p>0.05). No significant differences were observed in the specific peak twitch force between groups. Muscle fatigue was examined using 2Hz twitch contractions for 10 min. The fatigue profiles for the two groups were essentially identical, but half relaxation times were significantly prolonged by up to a 42% increase in mutant muscles compared to control muscles (p<0.05). Further, force frequency analysis showed significantly elevated force production in mutant muscles compared to controls from 10 to 80 Hz stimulation frequency (p<0.01). These results suggest that nBmp2 plays an important role in maintaining normal intracellular transport of calcium during skeletal muscle contraction and relaxation. Grant support: NIH AR48839
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