Exercise, mitochondrial dysfunction and inflammasomes in skeletal muscle

Slavin, Mikhaela B.; Khemraj, Priyanka; Hood, David A.

doi:10.1016/j.bj.2023.100636

Cited by 4 publications

(3 citation statements)

References 101 publications

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“…Recent studies have found that NLRP3 is an important regulator of skeletal muscle metabolism, and a growing amount of evidence shows that the NLRP3 inflammasome is involved in the pathogenesis and development of inflammation-related skeletal muscle atrophy [11,42]. Although there is little evidence showing the relationship between exercise and NLRP3 inflammasome activity in skeletal muscle, accumulating data suggests that exercise training improves cardiac function by suppressing inflammasome activity and cell death in the myocardium [43,44]. Our study found that exercise, and/or inhibition of NLRP3, increased muscle strength and exercise performance, reduced the protein expression levels of Atrogin1 and MuRF1 (Figure 3A,B) and further found that the combined effect of the two methods was best, indicating that NLRP3 may be a key factor in exercise for relieving diabetic muscle atrophy (Figure 2C).…”

Section: Mcc950 Treatment and Aerobic Exercise Moderates The Levels O...mentioning

confidence: 99%

MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise

Yan,

Fu,

Zhang

et al. 2024

Molecules

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Diabetic muscle atrophy is an inflammation-related complication of type-2 diabetes mellitus (T2DM). Even though regular exercise prevents further deterioration of atrophic status, there is no effective mediator available for treatment and the underlying cellular mechanisms are less explored. In this study, we investigated the therapeutic potential of MCC950, a specific, small-molecule inhibitor of NLRP3, to treat pyroptosis and diabetic muscle atrophy in mice. Furthermore, we used MCC950 to intervene in the protective effects of aerobic exercise against muscle atrophy in diabetic mice. Blood and gastrocnemius muscle (GAS) samples were collected after 12 weeks of intervention and the atrophic state was assessed. We initially corroborated a diabetic muscle atrophy phenotype in db/db mice (D) by comparison with control m/m mice (W) by examining parameters such as fasting blood glucose (D vs. W: 24.47 ± 0.45 mmol L−1 vs. 4.26 ± 0.6 mmol L−1, p < 0.05), grip strength (D vs. W: 166.87 ± 15.19 g vs. 191.76 ± 14.13 g, p < 0.05), exercise time (D vs. W: 1082.38 ± 104.67 s vs. 1716 ± 168.55 s, p < 0.05) and exercise speed to exhaustion (D vs. W: 24.25 ± 2.12 m min−1 vs. 34.75 ± 2.66 m min−1, p < 0.05), GAS wet weight (D vs. W: 0.07 ± 0.01 g vs. 0.13 ± 0.01 g, p < 0.05), the ratio of GAS wet weight to body weight (D vs. W: 0.18 ± 0.01% vs. 0.54 ± 0.02%, p < 0.05), and muscle fiber cross-sectional area (FCSA) (D vs. W: 1875 ± 368.19 µm2 vs. 2747.83 ± 406.44 µm2, p < 0.05). We found that both MCC950 (10 mg kg−1) treatment and exercise improved the atrophic parameters that had deteriorated in the db/db mice, inhibited serum inflammatory markers and significantly attenuated pyroptosis in atrophic GAS. In addition, a combined MCC950 treatment with exercise (DEI) exhibited a further improvement in glucose uptake capacity and muscle performance. This combined treatment also improved the FCSA of GAS muscle indicated by Laminin immunofluorescence compared to the group with the inhibitor treatment alone (DI) (DEI vs. DI: 2597 ± 310.97 vs. 1974.67 ± 326.15 µm2, p < 0.05) or exercise only (DE) (DEI vs. DE: 2597 ± 310.97 vs. 2006.33 ± 263.468 µm2, p < 0.05). Intriguingly, the combination of MCC950 treatment and exercise significantly reduced NLRP3-mediated inflammatory factors such as cleaved-Caspase-1, GSDMD-N and prevented apoptosis and pyroptosis in atrophic GAS. These findings for the first time demonstrate that targeting NLRP3-mediated pyroptosis with MCC950 improves diabetic muscle homeostasis and muscle function. We also report that inhibiting pyroptosis by MCC950 can enhance the beneficial effects of aerobic exercise on diabetic muscle atrophy. Since T2DM and muscle atrophy are age-related diseases, the young mice used in the current study do not seem to fully reflect the characteristics of diabetic muscle atrophy. Considering the fragile nature of db/db mice and for the complete implementation of the exercise intervention, we used relatively young db/db mice and the atrophic state in the mice was thoroughly confirmed. Taken together, the current study comprehensively investigated the therapeutic effect of NLRP3-mediated pyroptosis inhibited by MCC950 on diabetic muscle mass, strength and exercise performance, as well as the synergistic effects of MCC950 and exercise intervention, therefore providing a novel strategy for the treatment of the disease.

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Section: Mcc950 Treatment and Aerobic Exercise Moderates The Levels O...mentioning

confidence: 99%

MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise

Yan,

Fu,

Zhang

et al. 2024

Molecules

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“…Furthermore, exercise-induced NO release improves vascular function and cardiovascular health, even in patients with vascular diseases. NO also enhances mitochondrial biogenesis and efficiency, which is crucial for increasing endurance and reducing fatigue in prolonged activities [32]. Regular physical activity, therefore, not only helps maintain NO levels in aging but also leverages its benefits for cardiovascular and muscular health.…”

Section: Exploration Of the Role Of Nitric Oxide In Exercise Physiologymentioning

confidence: 99%

“…NO enhances blood flow, oxygen delivery, and muscle nutrient supply during exercise, improving performance and endurance. [32] Enzymes Mediating NO Production…”

Section: Examination Of the Consequences Of Excessive Nitrosative Str...mentioning

confidence: 99%

The Impact of Physical Exercise on Oxidative and Nitrosative Stress: Balancing the Benefits and Risks

Meng,

2024

Preprint

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This general review assesses the impact of physical exercise on oxidative and nitrosative stress and the counteractive role of antioxidants, drawing from a systematic literature search up to March 2024 in databases like PubMed and Web of Science. The review highlights studies on the effect of exercise on the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and antioxidant responses in both human and animal models based on rigorous inclusion and exclusion criteria. Due to the variety of exercise types and participants' characteristics, a narrative synthesis approach was adopted. The findings indicate that moderate exercise boosts antioxidant defenses, known as hormesis, whereas excessive physical activity may increase oxidative and nitrosative damage. The review also explores the complex effects of antioxidant supplementation, revealing that while natural dietary antioxidants support health, high-dose supplements could potentially hinder positive adaptations to exercise. Recommendations for athletes and the general active population highlight the importance of balancing exercise and dietary intake to optimize health benefits. The review concludes with a call for more detailed research on tailored exercise and nutrition plans to dissect these intricate relationships further.

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Evolutionary edge: NOD-like receptors in immunity

Kattner

2024

Biomedical Journal

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Exercise, mitochondrial dysfunction and inflammasomes in skeletal muscle

Cited by 4 publications

References 101 publications

MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise

MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise

The Impact of Physical Exercise on Oxidative and Nitrosative Stress: Balancing the Benefits and Risks

Evolutionary edge: NOD-like receptors in immunity

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