Silencing PIM1 inhibits ENO1-induced AKT activation and attenuates fibrillogenesis during spinal cord injury-induced skeletal muscle atrophy.

Abstract

Spinal cord injury (SCI) induces rapid and extensive skeletal muscle atrophy. During skeletal muscle atrophy, numerous extracellular matrix (ECM) and fibroblasts accumulate, impairing muscle function. The pro-viral Integration site for moloney murine leukaemia virus kinases-1(PIM1) is considered a positive regulator of inflammation. In our study, we found that PIM1 was overexpressed in the fibrotic regions of the skeletal muscle following SCI. We then explored the effects of the selective PIM1 inhibitor TP-3654 on fibrosis. TP-3654 decreased fibrosis by promoting fibroblast apoptosis, reducing proliferation and migration, and inhibiting tumor growth factor (TGF)-β classical and non-classical signaling pathways. In vivo PIM1 pharmacological inhibition with TP-3654 alleviates skeletal muscle fibrosis, mitigating skeletal muscle atrophy by decreasing ECM formation, enhancing the cross-sectional area of muscle fibers, and increasing muscle weight. Furthermore, we found a potential interaction between PIM1 and the enolase (ENO1)/protein kinase B (AKT) pathway. Downregulation of PIM1 expression in fibroblasts using drugs or siRNA leads to decreased ENO1 expression, concurrent with AKT phosphorylation reduction and suppressor of mothers against decapentaplegic (Smad)2/3 dephosphorylation within the TGF-β classical pathway. In summary, PIM1 might be an important target gene for future skeletal muscle atrophy treatments.