The influence of isoflavone for denervation-induced muscle atrophy.

PURPOSE: Decrease in activity stress induces skeletal muscle atrophy. A previous study showed that treatment with a high level (20%) of isoflavone inhibits muscle atrophy after short-term denervation (at 4 days) in mice. The present study was designed to elucidate whether the dietary isoflavone aglycone (AglyMax) at a 0.6% prevents denervation-mediated muscle atrophy, based on the modulation of atrogin-1- or apoptosis-dependent signaling. METHODS: Mice were fed either a normal diet or 0.6% AglyMax diet. One week later, the right sciatic nerve was cut. The wet weight, mean fiber area, amount of atrogin-1 and cleaved caspase-3 proteins, and the percentages of apoptotic nuclei were examined in the gastrocnemius muscle at 14 days after denervation. RESULTS: The 0.6% AglyMax diet significantly attenuated denervation-induced decreases in fiber atrophy but not the muscle wet weight. In addition, dietary isoflavone suppressed the denervation-induced apoptosis in spite of there being no significant changes in the amount of cleaved caspase-3 protein. In contrast, the 0.6% AglyMax diet did not significantly modulate the protein expression of atrogin-1 in the denervated muscle of mice. CONCLUSIONS: The isoflavone aglycone (AglyMax) at a 0.6% significantly would modulate muscle atrophy after denervation in mice, probably due to the decrease in apoptosis-dependent signaling.

Resveratrol attenuates denervation-induced muscle atrophy due to the blockade of atrogin-1 and p62 accumulation.

Decrease in activity stress induces skeletal muscle atrophy. A previous study showed that treatment with resveratrol inhibits muscular atrophy in mdx mice, a model of DMD. However, almost all studies using resveratrol supplementation have only looked at adaptive changes in the muscle weight. The present study was designed to elucidate whether the resveratrol-inducing attenuation of skeletal muscle actually reflects the adaptation of muscle fibers themselves, based on the modulation of atrogin-1- or p62-dependent signaling. Mice were fed either a normal diet or 0.5% resveratrol diet. One week later, the right sciatic nerve was cut. The wet weight, mean fiber area, and amount of atrogin-1 and p62 proteins were examined in the gastrocnemius muscle at 14 days after denervation. The 0.5% resveratrol diet significantly prevented denervation-induced decreases in both the muscle weight and fiber atrophy. In addition, dietary resveratrol suppressed the denervation-induced atrogin-1 and p62 immunoreactivity. In contrast, 0.5% resveratrol supplementation did not significantly modulate the total protein amount of atrogin-1 or p62 in the denervated muscle of mice. Resveratrol supplementation significantly prevents muscle atrophy after denervation in mice, possibly due to the decrease in atrogin-1 and p62-dependent signaling.

Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population.

N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed.

p62/SQSTM1 but not LC3 is accumulated in sarcopenic muscle of mice.

AIM: We investigated the pathway of autophagy signaling linked to sarcopenia of mice. METHODS: Young adult (3-month) and aged (24- month) C57BL/6J mice were used. Using real-time PCR, Western blotting, and immunohistochemical microscopy, we evaluated the amounts of p62/SQSTM1, LC3, and Beclin-1 in the quadriceps muscle change with aging in mice. RESULTS: Marked fiber atrophy (30%) and many fibers with central nuclei were observed in the aged mice. Western blotting using homogenate of the cytosolic fraction clearly showed that the amounts of p62/SQSTM1 and Beclin-1 proteins were significantly increased in the aged skeletal muscle. The amounts of these proteins in both nuclear and membrane fractions did not change significantly with age. Immunofluorescence labeling indicated that aged mice more frequently possessed p62/SQSTM1-positive fibers in the cytosol in quadriceps muscle than young ones (aged: 14% vs. young: 1%). In aged muscle, p62/SQSTM1-positive fibers were significantly smaller than the surrounding p62/SQSTM1-negative fibers. Aging did not elicit significant changes in the mRNA levels of p62/SQSTM1 and Beclin-1, but decreased LC3 mRNA level. In aged muscle, the location of p62/SQSTM1 immunoreactivity was similar to that of Beclin-1 protein, but not LC3. CONCLUSION: Sarcopenia in mice appears to include a marked defect of autophagy signaling.