Activating Striatal Parvalbumin Interneurons to Alleviate Chemotherapy-Induced Muscle Atrophy

Background

Cisplatin is a widely used chemotherapeutic agent for treating solid tumours. Still, it induces severe side effects, including muscle atrophy. Understanding the mechanisms of cisplatin-induced muscle loss and exploring potential therapeutic strategies are essential. Parvalbumin (PV) interneurons in the striatum play a crucial role in motor control, and recent studies suggest that their activation may alleviate motor deficits. This study investigates the effects of chemogenetic activation of PV interneurons on cisplatin-induced muscle atrophy and motor dysfunction in mice.

Methods

Wild-type C57BL/6 mice and transgenic hM3Dq mice were used in this study. Cisplatin (3 mg/kg) was administered intraperitoneally for 7 days to induce muscle atrophy. Mice were then treated with clozapine-n-oxide (CNO) to activate PV interneurons. Muscle strength and endurance were assessed using grip strength measurements, the inverted grid test and the wire hang test. Neuromuscular junction (NMJ) integrity was examined via histological analysis. Exercise intervention was also included, using a treadmill with a 15° incline for 60 min at varying speeds during seven consecutively days.

Results

Cisplatin treatment significantly reduced body weight (p < 0.001), grip strength (forelimb strength: p < 0.001, four-limb strength: p < 0.001), endurance (inverted grid test: p = 0.047, wire hang test: p = 0.014) and NMJ integrity (partially innervated NMJs: p = 0.0383). PV interneuron activation with CNO improved spontaneous motor activity in cisplatin-treated mice, as evidenced by a significant increase in total travel distance (p = 0.049) in the open-field test. Histological analysis showed a reduced ratio of partially innervated NMJs in the PV-cre group compared to the control virus group (p = 0.0441). Muscle strength also improved significantly, with forelimb grip strength increased (p < 0.001) and four-limb grip strength increased (p = 0.018). Muscle wet-weight ratios were significantly higher in the PV-cre group (quadriceps: p = 0.030). Exercise intervention significantly improved grip strength (forelimb: p < 0.001, four-limb: p = 0.002), muscle endurance (four-limb hang test: p = 0.048) and muscle weight (quadriceps: p = 0.015, gastrocnemius: p = 0.022), with an increase in muscle fibre cross-sectional area (p = 0.0018).

Conclusion

Activation of PV interneurons significantly alleviates cisplatin-induced motor deficits and muscle atrophy by improving spontaneous motor activity, NMJ integrity and muscle function. It has a similar effect to short-term exercise and may offer a promising therapeutic strategy for mitigating chemotherapy-induced muscle atrophy.