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GW8510 alleviates muscle atrophy and skeletal muscle dysfunction in mice through AMPK/PGC1α signaling
Yutong Chen1, Zurui Liu2, Chen Liu2
1Peking University International Cancer Institute, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China.
Abstract:
Preventing and restoring muscle loss and function is essential for elderly individuals. GW8510 may accelerate myotube differentiation. The present study aimed to investigate the protective effect of GW8510 (a CDK2 inhibitor) on muscle atrophy. Mouse models of muscle atrophy were induced by denervation, dexamethasone and glycerol. Muscle‑to‑body weight ratio, the cross‑sectional area of muscles, grip strength, fatigue and serum levels of superoxide dismutase and creatine kinase were assessed. In vitro, a dexamethasone‑induced C2C12 myotube atrophy model was used to evaluate mitochondrial function. Reverse transcription‑quantitative PCR, immunoblotting and small interfering RNA transfection were performed to explore the potential molecular mechanisms following treatment with GW8510. GW8510 resulted in a significant increase in the gastrocnemius and soleus muscle ratios in denervation mice (7 and 3%, respectively), alongside an increase in cross‑sectional area. Moreover, GW8510 significantly improved grip strength and superoxide dismutase activity, with similar protective effects in dexamethasone‑ and glycerol‑induced muscle atrophy models. GW8510 decreased reactive oxygen species production, increased mitochondrial DNA copy number, maintained mitochondrial dynamics and enhanced antioxidant activity in C2C12 myotubes. Mechanistically, GW8510 significantly inhibited the expression of atrophy‑associated markers F‑box protein 32 and tripartite motif‑containing 63 while activating AMPK (both P<0.01). The knockdown peroxisome proliferator‑activated receptor‑γ co‑activator‑1α (Pgc1α) negated the effects of GW8510. Overall, GW8510 mitigated muscle atrophy via the activation of the AMPK/PGC1α pathway. GW8510 could serve as a novel therapeutic agent for the prevention of muscle atrophy.
Insights
GW8510, a CDK2 inhibitor, effectively combats muscle atrophy by enhancing muscle mass, strength, and mitochondrial function. It activates the AMPK/PGC1α pathway, offering a potential therapeutic strategy for age-related muscle loss.
Area of Science:
- Muscle biology and aging research.
- Pharmacological interventions for sarcopenia.
Background:
- Muscle loss and functional decline are significant concerns for the elderly.
- Identifying novel therapeutic agents to prevent and restore muscle mass is crucial.
Purpose of the Study:
- To investigate the protective effects of GW8510, a CDK2 inhibitor, against muscle atrophy.
- To explore the underlying molecular mechanisms of GW8510 action.
Main Methods:
- Mouse models of muscle atrophy induced by denervation, dexamethasone, and glycerol.
- In vitro studies using a dexamethasone-induced C2C12 myotube atrophy model.
- Assessment of muscle mass, strength, mitochondrial function, and molecular pathways (AMPK, PGC1α).
Main Results:
- GW8510 significantly increased muscle ratios and cross-sectional area in denervated mice.
- Improved grip strength and antioxidant activity (superoxide dismutase) were observed across different atrophy models.
- GW8510 enhanced mitochondrial function and activated the AMPK/PGC1α pathway, inhibiting atrophy markers.
Conclusions:
- GW8510 mitigates muscle atrophy through the activation of the AMPK/PGC1α pathway.
- GW8510 demonstrates potential as a novel therapeutic agent for preventing muscle atrophy.
