Irisin as a biomarker of sarcopenia

Abstract

Sarcopenia is a gradual decrease of skeletal muscle mass and function during aging. Due to the absence of clear clinical indicator, it is required to develop useful biomarkers that can be quantified in a feasible, accessible manner and can accompany the diagnosis and therapy of pathological muscle atrophy in general clinical practices and trials. Recently, skeletal muscles have been established as an endocrine organ. Irisin is one of the myokines derived from skeletal muscle and is known to be induced upon vigorous exercise to facilitate thermogenesis of adipocyte. Furthermore, it is predominantly expressed in skeletal muscle compared to other tissues. The aims of this study are to determine whether atrophic and hypertrophic myotube remodeling alter irisin secretion level in vitro, and to assess the association of serum irisin level with sarcopenia in human. To investigate myotube diameter-dependent expression and secretion of irisin, I applied DEX and IGF-1 were applied to induce myotube atrophy or hypertrophy, respectively. Also, I tried to examine whether irisin functions as a trophic factor in vitro. In cross-sectional human study, we measured serum levels of irisin, as well as muscle mass and function in 715 Korean persons. The subjects were classified as sarcopenia using cutoff values of muscle weakness (HGS, male; < 30kg, female; < 20kg). In vitro studies, DEX and IGF-1 significantly induced myotube atrophy and hypertrophy, which result in decreased and increased irisin secretion levels, respectively. On the other hand, irisin treatment increased the phosphorylation of IGF-1 receptor in a time-dependent manner, attenuated DEX-induced down-regulation of FoxO3α phosphorylation, atrogin-1 up-regulation, and elevated proteasome activity in C2C12 myotubes. These results demonstrate a novel anti-atrophic function of irisin in muscle cells through suppression of FoxO/atrogenes-mediated ubiquitin proteasome pathway. In human study, serum irisin levels were lower in elderly groups compared to young adults, regardless of gender (elderly vs young adults, male; 1241±417 vs 1567±436 ng/mL, p < 0.05, female; 1336±485 vs. 1780±525 ng/ml, p < 0.05). This study also revealed that the serum irisin levels were significantly lower in the subjects with sarcopenia than normal group (sarcopenia vs. normal group, male; 1003±221 vs 1476±441 ng/mL, p < 0.05, female; 1210±471 vs. 1559±537 ng/ml, p < 0.05). In addition, serum irisin level was positively correlated with muscle mass and strength, and QMIs (e.g. FFM/BMI, male; r=0.252, p < 0.01, female; r=0.302, p < 0.01). The cut-off values of serum irisin to detect muscle weakness were determined as 1167.5 ng/ml (sensitivity: 0.760, specificity: 0.905) in men and 1175.2 ng/ml (sensitivity: 0.755, specificity: 0.583) in women. Taken together, the irisin secretion level is not only associated with trophic states of myotube in culture condition, but also might be related to muscle mass and function in human aging. Therefore, it may be considered as a potential biomarker for muscular atrophy / sarcopenia.