Mitochondrial Dysfunction and Changes of Myokine as a Mechanism of Age-related Sarcopenia

Abstract

Sarcopenia 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

18 males and 11 females) and old diseased (OD

5 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

however, 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.