PQQ ameliorates skeletal muscle atrophy, mitophagy and fiber type transition induced by denervation via inhibition of the inflammatory signaling pathways

Abstract

BACKGROUND: Skeletal muscle atrophy involves and requires widespread changes in skeletal muscle gene expression and signaling pathway, resulting in excessive loss of muscle mass and strength, which is associated with poor prognosis and the decline of life quality in several diseases. However, the treatment of skeletal muscle atrophy remains an unresolved challenge to this day. The aim of the present study was to investigate the influence of pyrroloquinoline quinone (PQQ), a redox-active o-quinone found in various foods and mammalian tissues, on skeletal muscle atrophy, and to explore the underlying molecular mechanism. METHODS: After denervation, mice were injected intraperitoneally with saline plus PQQ (5 mg/kg/d) or saline only for 14 days. The level of inflammatory cytokines in tibialis anterior (TA) muscles was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), and the level of signaling proteins of Janus kinase 2/signal transduction and activator of transcription 3 (Jak2/STAT3), TGF-β1/Smad3, JNK/p38 MAPK, and nuclear factor κB (NF-κB) signaling pathway were detected by Western blot. The skeletal muscle atrophy was evaluated by muscle wet weight ratio and cross-sectional areas (CSAs) of myofibers. The mitophagy was observed through transmission electron microscopy (TEM) analysis, and muscle fiber type transition was analyzed through fast myosin skeletal heavy chain antibody staining. RESULTS: The proinflammatory cytokines IL-6, IL-1β and TNF-α were largely induced in TA muscles after sciatic nerve transection. PQQ can significantly reverse this phenomenon, as evidenced by the decreased levels of proinflammatory cytokines IL-6, IL-1β and TNF-α. Moreover, PQQ could significantly attenuate the signal activation of Jak2/STAT3, TGF-β1/Smad3, JNK/p38 MAPK, and NF-κB in skeletal muscles after sciatic nerve transection. Furthermore, PQQ alleviated skeletal muscle atrophy, mitigated mitophagy and inhibited slow-to-fast muscle fiber type transition. CONCLUSIONS: These results suggested that PQQ could attenuate denervation-induced skeletal muscle atrophy, mitophagy and fiber type transition through suppressing the Jak2/STAT3, TGF-β1/Smad3, JNK/p38 MAPK, and NF-κB signaling pathways.