Identification and Validation of Novel Contraction-Regulated Myokines Released from Primary Human Skeletal Muscle Cells

Abstract

Proteins secreted by skeletal muscle, so called myokines, have been shown to affect muscle physiology and additionally exert systemic effects on other tissues and organs. Although recent profiling studies have identified numerous myokines, the amount of overlap from these studies indicates that the secretome of skeletal muscle is still incompletely characterized. One limitation of the models used is the lack of contraction, a central characteristic of muscle cells. Here we aimed to characterize the secretome of primary human myotubes by cytokine antibody arrays and to identify myokines regulated by contraction, which was induced by electrical pulse stimulation (EPS). In this study, we validated the regulation and release of two selected myokines, namely pigment epithelium derived factor (PEDF) and dipeptidyl peptidase 4 (DPP4), which were recently described as adipokines. This study reveals that both factors, DPP4 and PEDF, are secreted by primary human myotubes. PEDF is a contraction-regulated myokine, although PEDF serum levels from healthy young men decrease after 60 min cycling at VO2max of 70%. Most interestingly, we identified 52 novel myokines which have not been described before to be secreted by skeletal muscle cells. For 48 myokines we show that their release is regulated by contractile activity. This profiling study of the human skeletal muscle secretome expands the number of myokines, identifies novel contraction-regulated myokines and underlines the overlap between proteins which are adipokines as well as myokines.

Myokines in insulin resistance and type 2 diabetes

“…BDNF mRNA expression and protein has been detected in human skeletal muscle and C2C12 cells [46], and our group recently reported BDNF in the supernatant fraction of human myotubes [2]. While in patients with type 2 diabetes circulating levels of BDNF are decreased independently of obesity [47], exercise has been demonstrated to increase serum BDNF levels and BDNF mRNA and protein expression in human skeletal muscle [46].…”

“…The molecular background of this observation still needs to be determined. IL-15, which is expressed in skeletal muscle and released by myotubes [2,35], potentially plays a role in lipid metabolism. Conflicting results have been reported concerning the regulation of IL-15 expression in skeletal muscle and circulating IL-15 upon exercise.…”

“…Nowadays, skeletal muscle is recognised as an endocrine organ, and proteins expressed by and released from skeletal muscle have been termed myokines [1]. In three studies using primary human myotubes and proteomic approaches, hundreds of myokines have been identified, including more than 50 novel myokines [2][3][4].…”

Circulating irisin is lower in gestational diabetes mellitus

“…Then, the authors went through all references of received articles. Studies included in this meta-analysis had to meet all the following criteria: (1) papers reported the associations between circulating irisin and GDM; (2) casecontrol or cross-sectional investigation for GDM; (3) there should be at least two groups involved in a single study (GDM vs. control group). The flow chart for the identification of the studies is shown in Fig.…”

Dipeptidyl Peptidase-IV Activity and Neuropeptide Y in the Mouth: The Relationship with Body Composition and the Impact of Carbohydrates

“…A constant soluble DPP-IV activity in the plasma suggests that regulation of the activity level is controlled via a long-term mechanism. The mechanisms by which soluble DPP-IV in the plasma is controlled are currently unknown, but possible contributors are the muscle, fat, and T-cells [30][31][32].…”