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Mitochondrial Dysfunction and Changes of Myokine as a Mechanism of Age-related Sarcopenia : 가령에 따른 근감소증의 기전으로서의 미토콘드리아 기능이상 및 마이오카인의 변화

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dc.description학위논문 (박사)-- 서울대학교 대학원 : 의학과 분자유전체의학전공, 2015. 8. 최성희.-
dc.description.abstractSarcopenia is a phenomenon that accompanies aging. It is defined as the progressive loss of skeletal muscle quantity and quality. Sarcopenia reduces physical performance and enhances physical frailty in the elderly. In this study, we explore the possible mechanisms of sarcopenia by assessing the hypothesis that age-related sarcopenia in humans may be associated with changes in muscle mitochondria or changes in the expression and/or secretion of muscle secretory proteins, or myokine.
We recruited young diseased (YD
dc.description.abstract18 males and 11 females) and old diseased (OD-
dc.description.abstract5 males and 13 females) groups of both genders who underwent total hip replacement surgery due to osteoarthritis or avascular necrosis. Clinical characteristics were evaluated by assessing history, physical examination, body composition (determined by dual energy X-ray absorptiometry), and muscle strength (determined by isokinetic dynamometer). Serum concentrations of adipokines and myokines were measured by radioimmunoassay or quantitative enzyme immunoassay of fasting blood samples. Quantitative and qualitative evaluation of skeletal muscle mitochondria were determined by electron microscopy, light microscopy with immunohistochemical staining, spectrophotometric assay of mitochondrial respiratory chain activity, oxygen consumption measurement by high-resolution respirometry, and western blot analysis of mitochondrial complexes. Microarray analysis was performed to identify candidate mRNAs that encode proteins possibly involved in sarcopenia, and these candidates were subjected to real-time PCR. Finally, tissue expression profiles of interleukin (IL)-6 in young and old patients were compared in the skeletal muscle tissue by western blot analysis.
Average muscle mass in the unaffected leg of female subjects was significantly lower in OD than in YD. Muscle strength and quality were more significantly reduced in OD subjects than in YD subjects of both genders, but more strikingly in female subjects. Age was significantly correlated with muscle strength and quality in both genders. Muscle strength and quality showed marginal to significant negative correlations with physical dysfunction. Morphological changes of mitochondria were not observed in OD skeletal muscle. However, the number of mitochondria and the amount of complex protein were significantly higher in the OD group. Maximum oxidative capacity measured by high-resolution respirometry was not significantly lower in OD subjects than in YD subjects, but tended to be lower in the low muscle quality group than in the high muscle quality group. Complex I activity was significantly higher in the low muscle quality group and the OD group. Immunohistochemical staining indicated abnormal mitochondrial proliferation in OD muscle. There was no significant difference in IL-6 levels in serum and muscle tissue of OD and YD groups
dc.description.abstracthowever, both were significantly correlated with muscle strength. High IL-6 expression in muscle tissue seemed to be related to lower maximal oxidative capacity and higher compensatory expression of complex protein in mitochondria.
In conclusion, qualitative muscle deterioration is the main characteristic of age-related sarcopenia. This qualitative change in skeletal muscle is likely to be associated with qualitative change of mitochondria. Quantitative changes in mitochondrial numbers and complex protein levels seemed to occur as a compensatory mechanism for the aging-related qualitative changes. Serum and tissue IL-6 levels tended to increase with aging, and IL-6 levels negatively correlated with muscle strength. Thus, serum and tissue IL-6 might be involved in the development of age-related sarcopenia.
dc.description.tableofcontentsAbstract i
Table of Contents v
List of Tables viii
List of Figures x

I. Introduction 1

II. Materials & Methods 4
2.1. Subjects 4
2.2. Measurement of anthropometric parameters and body composition profile 5
2.3. Measurements of biochemical parameters 6
2.4. Muscle strength measurement 7
2.5. Evaluation for physical dysfunction 8
2.6. Comparison with functionally normal subjects 9
2.7 Muscle sample 9
2.8. Evaluation of mitochondrial morphology and function 10
2.9. Microarray 14
2.10. Quantitative real time PCR and western blot analysis 15
2.11. Statistical analysis 16

III. Results 18
3.1 Clinical characteristics of the study population 18
3.2 Body composition and muscle strength/quality of the study population 21
3.3. Correlations between age, muscle strength, and physical disability 23
3.4 Quantitative change in muscle mitochondria 26
3.5. Mitochondrial function in skeletal muscle 28
3.6 Immunohistochemistry staining of mitochondrial protein in muscles 32
3.7. Quantitative and qualitative features of mitochondria with respect to muscle strength 32
3.8. Microarray analysis of gene expression profiles 36
3.9. Evaluation of serum adipokines and myokines 38
3.10. Expression of mitochondrial proteins and myokines transcripts in skeletal muscles 38
3.11. Evaluation of the role of IL-6 in sarcopenia 40
3.12. Serum and tissue IL-6 levels negatively correlate with muscle strength 44
3.13. Relationship of tissue IL-6 expression with mitochondrial function and content 49

IV. Discussion 51
4.1. The characteristics of sarcopenia 51
4.2. Age-related mitochondrial changes in human skeletal muscle .54
4.3. Role of serum and tissue IL-6 in sarcopenia 58
4.4. Other candidate proteins that may be involved in sarcopenia 61
4.5. Discussion of methods 61
4.6 Further Investigations 64
4.7. Limitations 65

V. Conclusion 67

References 68

국문 초록 84
dc.format.extent22558701 bytes-
dc.publisher서울대학교 대학원-
dc.titleMitochondrial Dysfunction and Changes of Myokine as a Mechanism of Age-related Sarcopenia-
dc.title.alternative가령에 따른 근감소증의 기전으로서의 미토콘드리아 기능이상 및 마이오카인의 변화-
dc.citation.pagesix, 87-
dc.contributor.affiliation의과대학 의학과-
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