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OBJECTIVE:To investigate the efficacy of Sijunzi decoction (四君子汤) on limb weakness in a rat model of spleen Qi deficiency (SQD),and to study its effect on mitophagy in skeletal muscle through adenosine monophosphate-activated protein ki-nase (AMPK)/unc-51 like autophagy activating ki-nase 1 (ULK1) signaling.METHODS:SQD model rats were produced by fast-ing combined with forced swimming method for 15 d.After model assessment,rats were randomly divided into four groups of 10[low/middle/high (L/M/H) Sijunzi decoction dose groups and a normal saline (S) group].Limb holding power (HP) and body mass (BM) were measured after 2 weeks of treatment.Following euthanasia,quadriceps femo-ris were dissected and myofiber and mitochondrial morphology were observed by transmission elec-tron microscopy (TEM).Mitochondrial membrane potential (MMP),adenosine triphosphatase (ATP)and reactive oxygen species (ROS) levels were de-termined using colorimetric methods,and immu-noblot analysis of Microtubule-associated protein light chain 3 (LC3) and Sequestosome 1 (p62) was performed to monitor mitophagy and AMPK/ULK1 signaling.RESULTS:Compared with control (C) group rats,in the S group,HP was reduced,the myofiber Z line was disordered,mitochondria were scattered,and numerous vacuoles and mitophagy were observed.MMP and ATP levels were reduced,ROS levels were elevated,and LC3B expression,and p-AMPKα(Thr172)/AMPKα,p-ULK1 (Ser555)/ULK1,and p-Raptor (Ser792)/Raptor ratios were increased,while p62 expression and p-mTOR (Ser2448)/mTOR and p-ULK1 (Ser757)/ULK1 ratios were decreased.After treatment,compared with the S group,HP was improved in M and H groups but not in the L group.Mitophagy was reduced in M,H and L groups but the Z line was disordered and vacuoliza-tion remained in the L group.ATP levels were ele-vated in M,H and L groups,and MMPs were elevat-ed in M and H groups but not in the L group.ROS levels were decreased in M,H and L groups,as were LC3B expression and p-Raptor (Ser792)/Raptor ra-tios,while p62 expression and p-mTOR (Ser2448)/mTOR and p-ULK1 (Ser757)/ULK1 ratios were in-creased in M and H groups but not in the L group.p-AMPKα (Thr172)/AMPKα and p-ULK1 (Ser555)/ULK1 ratios were decreased in M,H and L groups.CONCLUSIONS:Sijunzi decoction improved HP,possibly by inhibiting mitophagy via suppression of AMPK/ULK1 signaling.This restored mitochondri-al morphology and improved oxidative phosphory-lation,which contributed to recovery of limb weak-ness in SQD model rats.