Yang Xin Shi Tablet Enhances Adaptability to Exercise Training by Relieving Statin-Induced Skeletal Muscle Injury

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Yang Xin Shi Tablet Enhances Adaptability to Exercise Training by Relieving Statin-Induced Skeletal Muscle Injury

Statins, widely prescribed for cardiovascular disease prevention, are associated with skeletal muscle complaints that limit their clinical utility. This study investigates the therapeutic potential of Yang Xin Shi Tablet (YXST), a traditional Chinese medicine formula, in alleviating simvastatin (SMV)-induced skeletal muscle injury while enhancing exercise adaptability in apolipoprotein E knockout (ApoE(^-)/(^-)) mice. The findings demonstrate YXST’s capacity to mitigate statin-related myotoxicity through modulation of mitochondrial function and energy metabolism pathways, offering a promising adjunctive therapy for patients requiring statin treatment.

Experimental Design and Methodology

ApoE(^-)/(^-) mice fed a high-fat diet were randomized into four groups after four weeks:

  1. Exercise: Exercise training alone.
  2. Exercise + SMV: Exercise + 20 mg/kg/day simvastatin.
  3. Exercise + SMV + LYXST: Exercise + SMV + 750 mg/kg/day YXST.
  4. Exercise + SMV + HYXST: Exercise + SMV + 1500 mg/kg/day YXST.

Treatments were administered via gavage for eight weeks. Exercise capacity was evaluated using a running tolerance test. Plasma biomarkers (total cholesterol, creatine kinase) and skeletal muscle morphology (gastrocnemius histology) were analyzed. Glycogen reserves, mitochondrial Complex III activity, and molecular markers (AMPK, PGC-1α, NRF1, TFAM) were assessed to elucidate mechanisms.

Key Findings

1. Lipid-Lowering Efficacy and Muscle Protection

YXST did not interfere with simvastatin’s lipid-lowering effects. Total cholesterol levels remained comparable across SMV-treated groups:

  • Exercise + SMV: 22.54 ± 2.76 mg/dL
  • Exercise + SMV + LYXST: 25.75 ± 3.21 mg/dL
  • Exercise + SMV + HYXST: 22.51 ± 2.01 mg/dL
    (All values significantly lower than Exercise group: 41.68 ± 9.62 mg/dL, P < 0.05).

Notably, YXST reversed SMV-induced exercise intolerance. Running tolerance improved by 68% in HYXST (1095.25 ± 237.10 seconds) and 58% in LYXST (1030.80 ± 150.28 seconds) compared to SMV alone (652.50 ± 169.40 seconds, P < 0.05).

2. Mitigation of Muscle Injury

YXST reduced plasma creatine kinase (CK), a biomarker of muscle damage, by 58% (HYXST: 0.35 ± 0.06 U/L) and 60% (LYXST: 0.38 ± 0.06 U/L) relative to SMV (0.91 ± 0.20 U/L, P < 0.05). Histological analysis revealed denser, less atrophic muscle fibers in YXST-treated mice (Figure 1E), corroborating its protective role against statin-induced myolysis.

3. Restoration of Energy Metabolism

Statin-induced impairment of glycogen utilization and mitochondrial function was reversed by YXST. Periodic acid-Schiff (PAS) staining showed increased glycogen reserves in YXST groups (Figure 1F). Mitochondrial Complex III activity, suppressed by SMV (5.72 ± 0.80 vs. 2.06 ± 0.85 U/mg protein, P < 0.05), was restored to 11.51 ± 1.97 U/mg (HYXST) and 8.21 ± 1.77 U/mg (LYXST) (P < 0.05 vs. SMV, Figure 1D).

4. Activation of AMPK-PGC-1α Signaling Pathway

YXST enhanced phosphorylation of AMPK (p-AMPK) and PGC-1α (p-PGC-1α), critical regulators of mitochondrial biogenesis. Western blot analysis showed:

  • p-AMPK/AMPK ratio: Increased from 0.46 ± 0.08 (SMV) to 0.64 ± 0.09 (HYXST, P < 0.05).
  • p-PGC-1α/PGC-1α ratio: Elevated from 0.70 ± 0.10 (SMV) to 0.88 ± 0.07 (HYXST) and 0.87 ± 0.09 (LYXST, P < 0.05, Figure 1G).

Downstream targets NRF1 and TFAM, essential for mitochondrial DNA transcription, were upregulated:

  • NRF1 mRNA: 0.87 ± 0.09 (HYXST) vs. 0.64 ± 0.07 (SMV, P < 0.05).
  • TFAM mRNA: 1.20 ± 0.11 (HYXST) and 1.03 ± 0.13 (LYXST) vs. 0.69 ± 0.09 (SMV, P < 0.05, Figure 1H).

Mechanistic Insights

The AMPK-PGC-1α pathway activation by YXST enhances mitochondrial biogenesis and oxidative metabolism, counteracting statin-induced energy deficits. By restoring Complex III activity (a known off-target of statins) and glycogen utilization, YXST addresses both mitochondrial dysfunction and substrate depletion implicated in statin myopathy.

Clinical Implications

Elderly patients on long-term statin therapy often experience reduced exercise capacity and muscle strength, increasing fall risk. YXST’s dual ability to preserve statin efficacy while mitigating myotoxicity positions it as a viable adjunct for cardiovascular patients requiring exercise rehabilitation.

Conclusion

This study demonstrates that YXST alleviates statin-associated skeletal muscle injury through mitochondrial protection and metabolic enhancement. By activating AMPK-PGC-1α signaling, YXST restores energy homeostasis and exercise tolerance without compromising lipid-lowering benefits. These findings support further clinical evaluation of YXST as a complementary therapy for statin-treated patients.

doi.org/10.1097/CM9.0000000000001028

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