ビタミンD, アミノ酸による炎症制御機構とサルコペニア治療可能性の検討

学位の種別:課程博士University of Tokyo(東京大学

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy

BackgroundInterleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear.\nMethodsTail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy.ResultsSerum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice.ConclusionSystemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy

Exercise-induced vitamin D receptor and androgen receptor mediate inhibition of IL-6 and STAT3 in muscle

Background: Skeletal muscle produces interleukin-6 (IL-6) during exercise as a myokine. Although IL-6 is required for skeletal muscle regeneration, its action increases the expression of myostatin and other proteins involved in muscle atrophy, resulting in skeletal muscle atrophy. In this study, we clarified the effects exercise-induced vitamin D receptor (VDR) and androgen receptor (AR) expression on IL-6 and signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro. Method: C2C12 myotubes were subjected to electric pulse stimulation (EPS) in vitro. To evaluate VDR and AR function, a VDR/AR agonist and antagonist were administered before EPS to C2C12 myotubes. C57BL6 mice underwent 4 weeks of exercise. The expression levels of proteolytic-associated genes, including CCAAT/enhancer-binding protein delta (C/EBPδ) and myostatin, were measured by quantitative real-time polymerase chain reaction, and phosphorylated and total STAT3 levels were measured by Western blot analysis. Result: The expression of VDR and AR mRNA was induced following EPS in C2C12 myotubes. IL-6 mRNA expression was also increased with a peak at 6 h after EPS and p-STAT3/STAT3 ratio reciprocally decreased. Although VDR/AR agonist administration decreased IL-6 mRNA expression and p-STAT3/STAT3 ratio, these two endpoints increased after treatment with VDR/AR antagonist, respectively. Exercise in mice also increased the expression of VDR/AR and IL-6 mRNA and decreased p-STAT3/STAT3 ratio. Conclusion: Exercise-induced VDR and AR expression results in the suppression of IL-6 mRNA and STAT3 phosphorylation in skeletal muscle

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy.

Interleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear.Tail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy.Serum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice.Systemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy

Sex-related differences in the effects of nutritional status and body composition on functional disability in the elderly.

BackgroundThe aim of our study was to evaluate the influence of changes of nutritional status and body composition on the results of comprehensive geriatric assessment (CGA) in inpatients of a geriatric ward. Sex differences in these relationships were also investigated.MethodsA total of 212 elderly patients (>65 years old) admitted to the geriatric ward at the University of Tokyo hospital between 2012 and 2019 were enrolled in this study. CGA (ADL, IADL, MMSE, GDS, Vitality Index) was performed, along with assessment of body compositions (appendicular muscle mass, abdominal muscle mass, body fat mass) and blood malnutrition biomarkers (serum albumin, pre-albumin, 25-hydroxy vitamin D, zinc, hemoglobin concentrations).ResultsMultiple linear regression analysis showed that upper, lower limbs and abdominal muscle masses were significantly associated with the score on ADL in men. On the other hand, abdominal muscle mass was negatively associated with the scores on GDS. Body fat mass was also negatively associated with the score on IADL. In contrast, in women, multiple linear regression analysis failed to show any significant associations between body composition parameters and scores on any domains of CGA. Unlike in men, however, blood malnutrition biomarkers were significantly associated with ADL, IADL, MMSE, and Vitality Index in women.ConclusionsOur study findings revealed that the association of the nutritional status and body composition with the functional status in the elderly differs by sex. These results suggest that intensification of exercise in men and improvement of the nutritional status in women are particularly useful to maintain the functional status

Characteristics of tail-suspended mice and aged mice.

<p>(A) Twelve-week-old C57BL/6J male mice were subjected to two weeks of tail suspension. Mice were sacrificed, and then serum samples and soleus muscles were collected. Serum IL-6 level was determined using ELISA. Soleus muscle weight/body weight ratio and the body weight of mice are shown (n = 4). (B) Twelve-week-old mice were subjected to seven days of tail suspension, and then RNA was extracted from the following tissues: whole bone marrow from femurs (n = 4), soleus muscles (n = 3), livers (n = 6), spleens (n = 3), and small intestines (n = 3). Quantitative real-time PCR was performed, and the relative IL-6 expression in each tissue is shown. (C) C57BL/6J male mice aged 15 weeks and 104 weeks were sacrificed, and then serum samples and soleus muscles were collected (n = 4). *p<0.05, **p<0.01, n.s.: not significant.</p

Effects of 1,25(OH)₂D₃ and HMB on the tail suspension-induced serum IL-6 surge.

<p>Twelve-week-old C57BL/6J male mice were administered 1,25(OH)₂D₃, HMB or both by gavage for seven days and then subjected to two weeks of tail suspension. Serum IL-6 level was determined by ELISA. n = 4, **p<0.01.</p

Prescription of vitamin D was associated with a lower incidence of hip fractures

Abstract Patients with osteoporosis are prone to fragility fractures. Evidence of the effects of active forms of vitamin D on hip fracture prevention is insufficient. We examined the association between vitamin D prescription and incidence of new fractures using the data of osteoporotic patients from the nationwide health insurance claims database of Japan. The follow-up period was 3 years after entry. The untreated patients were never prescribed vitamin D during follow-up (n = 422,454), and the treated patients had a vitamin D medication possession ratio of ≥ 0.5 at all time points (n = 169,774). Propensity score matching was implemented on these groups, yielding 105,041 pairs, and subsequently, the control and treatment groups were established and analyzed. The incidence of new fractures was significantly lower in the treatment group compared with the control group (6.25% vs. 5.69%, hazard ratio 0.936 [95% confidence interval 0.904–0.970], p < 0.001*). By site, hip fractures significantly decreased (0.89% vs. 0.42%, p < 0.001), but not vertebral and radial fractures. Subgroup analysis by vitamin D type showed a significantly lower incidence of total fractures only in alfacalcidol (hazard ratio 0.676 [95% confidence interval 0.628–0.728], p < 0.001*). The results suggest that vitamin D prescription was associated with a reduced incidence of hip fractures