Pro-inflammatory cytokines as regulators of protein tyrosine phosphatases and insulin signaling in murine skeletal muscle cells

Abstract

Inflammatory processes can disrupt tissue homeostasis and promote metabolic disturbances, including insulin resistance. Pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), mediate this process. Since skeletal muscle is one of the major insulin-sensitive tissues, it is crucial to search for molecular links that promote insulin resistance during inflammation. Protein tyrosine phosphatases (PTPs) negatively regulate insulin signaling in multiple organs and models. To gain insight into the potential interactions of cytokines and PTPs in skeletal muscle, we characterized the effects and kinetics of cytokine stimulation on insulin signaling in murine C2C12 muscle cells. The protein level and activities of PTP non-receptor type 1 (PTPN1/PTP1B) and type 2 (PTPN2/TCPTP) were evaluated after cytokine stimulation and addressed by pharmacological inhibition or siRNA-mediated knockdown (KD). TNF, IL-1β and IL-6 elicited different kinetics and expression patterns of the respective PTPs and insulin signaling molecules, while surprisingly, insulin action was preserved. Furthermore, PTPN1 and PTPN2 had only minor effects on insulin signaling in C2C12 cells with siRNA-mediated compensatory PTP regulation. However, pan-PTP inhibition by sodium orthovanadate confirms that PTPs are negative regulators of insulin signaling. In summary, our data provide insights into the balance of the physiological and pathophysiological effects of cytokines and targeting individual PTPs to regulate insulin signaling in C2C12 cells. Additionally, our findings highlight the complex dynamics and interplay of cytokines, PTPs and metabolic pathways. This should be acknowledged when new therapeutic tools are developed to address inflammation-induced diseases such as type 2 diabetes or related comorbidities.

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