Abstract
Type 1 diabetes mellitus is an autoimmune disease caused by the destruction of pancreatic beta cells. Many patients with type 1 diabetes experience skeletal muscle wasting. Although the link between type 1 diabetes and muscle wasting is not clearly known, insulin insufficiency and hyperglycemia may contribute to decreased muscle mass. In this study, we investigated the therapeutic effect of the ethanolic extract of Schisandrae chinensis Fructus (SFe) on muscle wasting in streptozotocin (STZ)-induced diabetic mice. STZ-diabetic C57BL/6 mice (blood glucose level ≥300 mg/dL) were orally administered SFe (250 or 500 mg/kg/day) for 6 weeks. We observed that SFe administration did not change blood glucose levels but increased gastrocnemius muscle weight, cross-sectional area, and grip strength in STZ-induced diabetic mice. Administration of SFe (500 mg/kg) decreased the expression of atrophic factors, such as MuRF1 and atrogin-1, but did not alter the expression of muscle synthetic factors. Further studies showed that SFe administration decreased the expression of KLF15 and p-CREB, which are upstream molecules of atrophic factors. Examination of the expression of molecules involved in autophagy–lysosomal pathways (e.g., p62/SQSTM1, Atg7, Beclin-1, ULK-1, LC3-I, and LC3-II) revealed that SFe administration significantly decreased the expression of p62/SQSTM1, LC3-I, and LC3-II; however, no changes were observed in the expression of Atg7, Beclin-1, or ULK-1. Our results suggest that SFe ameliorated muscle wasting in STZ-induced diabetic mice by decreasing protein degradation via downregulation of the CREB-KLF15-mediated UPS system and the p62/SQSTM1-mediated autophagy–lysosomal pathway.
Highlights
Skeletal muscle atrophy is characterized by the loss of muscle mass and muscle function and has many causes, such as aging, prolonged disuse, malnutrition, and various diseases [1,2]
We found that SFe inhibits muscle wasting by suppressing protein degradation through the cAMP response element binding protein (CREB)-Krüppel-like factor 15 (KLF15)-mediated ubiquitin–proteasome system (UPS) system and the p62/SQSTM1-mediated autophagy–lysosomal pathway
To evaluate whether SFe exerts beneficial effects on muscle wasting in STZ-induced diabetic mice, we administered SFe for 6 weeks to STZ-induced diabetic mice with blood glucose levels over 300 mg/dL
Summary
Skeletal muscle atrophy is characterized by the loss of muscle mass and muscle function and has many causes, such as aging, prolonged disuse, malnutrition, and various diseases (e.g., cancer, diabetes, and chronic kidney disease) [1,2]. Muscle atrophy adversely affects quality of life and increases morbidity and mortality [3], recovery of muscle mass and strength is essential for increasing physical performance and maintaining quality of life. Several methods have been implemented for muscle atrophy treatment. These include physical therapy such as stretching, endurance and resistance exercises to prevent immobility, functional electric stimulation for muscle contraction, or surgery in patients with muscle atrophy resulting from neurological problems [4]. Proven largely ineffective for the treatment of muscle atrophy, leading many researchers to explore novel medication methods [5].
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