KPC1 dishomeostasis-mediated by sympathetic nervous system over-excitement involved in myofiber types alteration and insulin resistance through NF-KB signaling pathway

Whether sympathetic over-activity involved in skeletal muscle insulin resistance and development of type 2 diabetes (T2DM) through affecting the differentiation and fusion of skeletal muscle satellite cells and changes in muscle fiber types, is still unknown. KPC1 deficiency deteriorated norepinephrine (NE)-induced loss of slow-twitch type I myofibers by micro osmotic pump (MP) and increased insulin resistance in mice. Continuous single dose (CS) and MP administration of NE and epinephrine (E) have been created, showing the inhibitory effects on C2C12 myoblast cells differentiation/fusion and type I slow-twitch fiber formation and glucose transporter type 4, glucose transport and uptake in vitro , matching with the changes of skeletal muscle fiber types in early and late T2DM in vivo , respectively. Notably, KPC1 expression showed the unique expression mode that it was gradually increased, reaching peak value on the fourth day, and then gradually decreased during the process of myoblast cells differentiation/fusion and myofiber formation. Furthermore, over-expression of KPC1 on third day, not zero day, showed the almost complete reversal effect on the inhibitory role of NE in myoblast cells differentiation/fusion and type I slow-twitch fiber formation, indicating KPC1’ specific time and dosage mode of action. Mechanistic studies revealed that NE reduced KPC1 and NF-KBp50/p65 protein levels, especially in the NF-KBp50 nucleation distribution. Curiously, E increased KPC1 and NF-KBp50 protein levels while unchanged NF-KBp65 levels, but showing the similar inhibitory effects on myoblast cells differentiation/fusion and slow-twitch type I myofiber formation. NE or E-mediated inhibitory role in myoblast differentiation/fusion could be worsen by NF-KBp50 inhibitor SN50, but partially abolished by NF-KBp65 blocker PDTC. Taken together, over-excitation of the sympathetic nervous system disturbed the balance between KPC1's time and dosage to cause the common inhibitory role in myoblast differentiation/fusion and slow-twitch fiber formation and glucose utilization, which were associated with abnormal matching of NF-KBp50/p65 signaling.