Akt x FBXO32 x TRIM63 x mTOR

Anemarrhena asphodeloides is a traditional herbal medicine for treating respiratory disorders. Cigarette smoke (CS) exposure is closely associated with increased risk of skeletal muscle atrophy.

We isolated a bioactive polysaccharide from Anemarrhena asphodeloides and investigated its efficacy in attenuating CS-induced sarcopenia and the underlying mechanisms.

Bioactivity-guided isolation approach was used to purify AAP-C1, a bioactive polysaccharide from Anemarrhena asphodeloides. Spectroscopic and chromatographic analyses were performed to characterize its structural details. CS-exposed C2C12 myoblasts and model mice were used to evaluate the therapeutic effects of AAP-C1 on skeletal muscle atrophy and elucidate the underlying molecular mechanisms.

Structural analysis identified AAP-C1 as a heteropolysaccharide (Molecular weight: 3.2 kDa) with fructose and glucose residues in a molar ratio of 18.6:1. AAP-C1 consists of a backbone with →1)-β-D-Fruf-(2→, →6)-β-D-Fruf-(2→, and →6)-α-D-Glcp-(1→ units and β-D-Fruf-(2→ side chains at O-6 positions. AAP-C1 enhanced myoblast proliferation by upregulating myogenic regulators (MyoD1 and MHC) and suppressing muscle proteolysis markers (MuRF-1 and Atrogin1) in the CS-exposed C2C12 cells. AAP-C1 treatment improved muscle function in the CS-exposed mice, as evidenced by increased grip strength, climbing endurance, and wheel-running activity. Mechanistically, AAP-C1 promoted MyoD1-mediated myogenesis by activating the Akt/mTOR signaling pathway. Concurrently, AAP-C1 inhibited the ubiquitin-proteasome pathway by reducing the expression levels of muscle atrophy-related ubiquitin ligases.

AAP-C1 ameliorates CS-induced sarcopenia by inducing myogenic differentiation and inhibiting ubiquitin-proteasome-mediated proteolysis through activation of the Akt/mTOR signaling pathway. Therefore, AAP-C1 demonstrates immense therapeutic potential in alleviating CS-related muscle atrophy.

Muscle atrophy after the rupture of a rotator cuff (RC) tendon is a major factor that increases the risk of secondary complications and rerupture. Metformin, a type 2 diabetes treatment, can be used to modulate intracellular signaling pathways that promote muscle growth. This study aimed to verify whether systemic metformin administration could prevent supraspinatus (SS) atrophy after RC rupture in a rat model.

This study is a comparative animal study aimed at investigating the effects of metformin. Twelve-week-old male Sprague-Dawley rats were used. The metformin group was administered intraperitoneal injection with 50 mg/kg metformin daily for 6 weeks after the RC tendon was cut, while the control group was given 0.9% saline solution. All rats were weighed and sacrificed 6 weeks after their surgery; then, SS were collected, and individual SS weights were measured. The expression of muscle atrophy genes was determined through quantitative reverse transcription polymerase chain reaction, and the amount of signal metabolism regulatory protein was measured by western blotting. Muscle atrophy and fatty infiltration (FI) were evaluated by histological staining.

Six weeks after RC tendon rupture, the SS weight in the metformin group was significantly higher than in the control group. Western blotting analysis revealed that the expression levels of phosphatidylinositol 3-kinase (P = .002), protein kinase B (P = .001), and mammalian targets of rapamycin (P = .009) protein were significantly higher in the metformin group than in the control group. The muscle atrophy-related marker genes Atrogin-1 (P = .036) and muscle-specific ring finger protein 1 (P < .000) in the metformin group were downregulated. The morphology of the SS, whose atrophy was prevented by metformin, had fewer wide pores and less reduced muscle fiber area than those of the control group. Muscle tissue staining analysis showed that FI was significantly suppressed by systemic metformin administration compared with that of the control group both qualitatively and quantitatively (P = .032). Metformin elicited an FI-suppressing effect by downregulating the adipogenic genes peroxisome proliferator-activated receptor gamma (P = .001) and CCAAT/enhancer-binding protein alpha (P < .001).

Metformin significantly prevented SS atrophy by activating the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway in an acute RC tear rat model. It also suppressed FI by downregulating adipogenic factors in the late stage of RC tear. These results strongly supported the usefulness of metformin for high-quality muscle preservation after RC rupture in clinical practice.

Skeletal muscle mass is significantly negatively regulated by glucocorticoids. Following glucocorticoid administration, the balance between protein synthesis and breakdown in skeletal muscle is disrupted, shifting towards a predominance of catabolic metabolism. Short‐chain fatty acids like sodium butyrate have been found to regulate inflammatory reactions and successively activate signaling pathways. The preventive benefits of sodium butyrate against dexamethasone‐induced skeletal muscle atrophy and myotube atrophy models were examined in this work, and the underlying mechanism was clarified. A total of 32 6‐week‐old C57BL/6 inbred male mice were randomly assigned to one of four groups and treated with dexamethasone to induce muscle atrophy and sodium butyrate. We found that sodium succinate alleviated dexamethasone‐induced myotube atrophy in the myotube atrophy model by lowering the gene expression of two E3 ubiquitin ligases, Atrogin‐1 and MURF1, and activating the AKT/mTOR signaling pathway. Pertussis toxin reversed this effect, indicating that G protein‐coupled receptors were involved in sodium butyrate's action as a mediator. Additionally, pre‐treatment with sodium butyrate lowered weight and muscle mass loss in a mouse model of skeletal muscle atrophy, dramatically decreased the MURF1 gene expression and decreased the nuclear translocation of the glucocorticoid receptor. In conclusion, this study shows that sodium butyrate inhibits the expression of atrophy genes, thus preventing the breakdown of proteins and the loss of muscle mass, while also inhibiting weight loss, in animal models.