Moderate Exercise Suppresses NF-κB Signaling and Activates the SIRT1-AMPK-PGC1α Axis to Attenuate Muscle Loss in Diabetic db/db Mice
Open accessAbstract
The clear mechanism of moderate exercise training (Ex) in attenuating muscle loss remains elusive in diabetes. We investigated the effects of moderate exercise training on diabetes-induced nuclear factor-κB (NF-κB) activation and mitochondrial dysfunction. Skeletal muscle size and atrophy signaling pathways were examined in type 2 diabetic db/db mice with or without moderate exercise training (5.2m/min, 1h/day, and 5days/week for a total of 8weeks). Exercise training decreased serum leptin, MCP-1, and resistin levels in db/db+Ex mice, but it did not reduce symptoms of insulin resistance including hyperglycemia, hyperinsulinemia, and impaired glucose tolerance. Moderate exercise training prevented the loss of muscle mass of tibialis anterior and gastrocnemius muscles in db/db+Ex mice. The average cross-sectional area of tibialis anterior muscle was increased significantly in db/db+Ex mice compared with untrained mice (830.6 vs.676.5 μm2). Inhibition of MuRF-1 and K48-linked polyubiquitination was observed in db/db+Ex mice. Exercise training reduced activation of IkBa/NF-kB pathway and lowered IL-6, TNF, F4/80(macrophage marker) at mRNA level in db/db+Ex mice compared with untrained mice. Exercise training did not influence FoxO3a phosphorylation and its upstream regulator Akt. Exercise training increased SIRT1 and PGC1a expression and AMPK and mitochondrial complex IV activities and upregulated genes involved in mitochondrial biogenesis/function including Nrf1, Tfam, and mitochondrial complexes I-V. In conclusion, moderate exercise training inhibits NF-kB signaling and activates SIRT1-AMPKa-PGC1a axis, thereby attenuating type 2 diabetes-related muscle atrophy.
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“Additionally, one study reported that exercise decreased the activation of the IκBa/ NF-κB pathway in diabetic mice (Liu and Chang 2018).”
Physical Activity as an Adjunct Treatment for People Living with HIV?
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“Whereas an acute bout of exercise was associated with acute activation of NF-kB, acclimation to regular exercise suppressed NF-kB in mice models and prevented nonresolving inflammation.(114) Physical activity thus offers great promise as a potential lifestyle modification for reducing nonresolving inflammation and inf…”
BackgroundComplementary Approaches to Retinal Health Focusing on Diabetic Retinopathy
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“In T2DM, lifestyle modifications, such as moderate exercise, may help main‑ tain muscle health [115].”
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Mitochondria as a target for exercise-mitigated type 2 diabetes
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“Exercise, energy restriction, muscle contraction and other stimuli were proven to decrease ATP/ADP ratio and increase AMP level, AMPK could be activated when AMP increased to a certain extent, which then activated Sirt1, PGC-1α (Liu and Chang 2018), and promoted mitochondrial biogenesis (Jeon 2016).”
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“Physical exercise inhibits inflammation-activated NF-κ B/MAPK signaling [29–31].”
BackgroundThe multifaceted impact of physical exercise on FoxO signaling pathways
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“NF-κB repression curtailed MuRF1 transcription, while a SIRT1/AMPK/PGC-1α axis boosted mitochondrial biogenesis and oxidative capacity, decreasing diabetes-induced wasting (Liu and Chang, 2018).”
Bioinformatic analysis of the gene expression profile in muscle atrophy after spinal cord injury
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The effect of physical activity on anti-infection immunity: a review
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Comparison of sirtuin 1 level and related blood factors in diabetic and healthy subjects
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“In b-cellspecific SIRT1 over-expression (BESTO) mice, higher SIRT1 levels improve glucose tolerance and increase insulin secretion [18, 19].”
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“Alternatively, exercise training decreases TLR expression, while stimulating the expression of antioxidant enzymes and sirtuin 1 (SIRT1), which inhibits NF-κB activity through deacetylation and induces PPARα signaling pathway activation (Gleeson et al., 2006; Liu and Chang, 2018).”
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Alfaro, E., Díaz‐García, E., García-Tovar, S., Galera, R., Casitas, R., Martínez-Cerón, E., Torres-Vargas, M., Padilla, J. M., Fernández, C. L., Pérez-Moreno, P., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-31223-7 · Cited by 3 · see citing works
“Regular physical activity may mitigate these processes by improving respiratory function, reducing hypoxia and systemic inflammation 41,42 , and enhancing the expansion of regulatory T cells, thereby limiting excessive T cell activation 43 .”
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“For instance, in Liu and Chang’s work, cytochrome C oxidase activity was lower in diabetic mice, and exercise stimulation contributed to an increase in mRNA levels of mitochondrial complexes subunits, through the induction of PGC1 α , NRF1, and TFAM levels [64].”
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“Exercise is known to suppress NF-κB activation and reduce inflammatory gene expression [28]; however, the persistent cellular stress and inflammation in AD likely sustain elevated NF-κB activity.”
Aerobic exercise improves spatial memory in a rat model of meningitis
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“Aerobic exercise reduces the activation of the inhibitor of kappa B alpha ( IκBα )/ NF-κB pathway and decreases IL-6, TNFα, and F4/80 (macrophage markers) at the mRNA level in db/db+Ex [39].”
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“…m u s c l e t i ss u e P o l a r i z a t i o n M 1 i n t o M 2 a n d i n v o l v i n g m u s c l e r e p a i r a n d r e g e n e r a t i o n [ 94 – 97 ] International Journal of Hypertension subtype occurred through immune complexes, toll-like receptors (TLRs) agonists, or IL-1 receptor agonists…”
Exercise alleviates symptoms of CNS lupus
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Vladimirsky, V. E., Vladimirsky, E. V., Lunina, A. N., Fesyun, A. D., Rachin, A. P., Lebedeva, O. D., Yakovlev, M. Y., & Аркадьевна, Т. М. (2022) · Problems of Balneology Physiotherapy and Exercise Therapy · doi:10.17116/kurort20229902169 · Cited by 2 · see citing works
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“Eight weeks of moderateintensity aerobic training resulted in a significant decrease in TNF-α levels as well as a decrease in activation of the IκBα/NF-κB pathway (19).”
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“Although the contractile muscle activity during exercise also contributes to enhancing the NFκB levels (Kramer and Goodyear, 2007), moderate exercise training decreases NF-κB activation (Liu and Chang, 2018).”
BackgroundThe effectiveness of physical activity in cardiorehabilitation
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“Moreover, exercise training enhances the expression of the SIRT1-AMPK-PGC-1α axis, while suppressing NFκB signaling, further improving mitochondrial oxidative phosphorylation and biogenesis, in diabetic heart [32].”
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“In this regard, Liu et al found that moderate-intensity endurance training could significantly reduce NF-KB in diabetic rats (34).”
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“De duidelijkste effecten van aerobe training zijn gevonden bij type-2-diabetes [41], waarbij de leidende gedachte is dat inspanning (mits geen overbelasting of overtraining) anti-inflammatoir werkt [42].”
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“PGC-1α and AKT signaling are the most important inhibitors of FOXO1 (8, 32, 33).”
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“In diabetic db/db mice moderate intensity trainings for eight weeks significantly reduced mRNA levels of TNFα, IL- 6, and F4/80 (macrophage marker) as well as reduced activation of IκBα/NF-κB pathway (32).”
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“Therefore, decreased fat mass and TNF-α level, suppression of the Nuclear Factor-kappaB (NF-kB) signaling pathway, and reduced insulin resistance induced by exercise can be the possible causes of the effect of exercise on the adiponectin level in obese girls [12, 16, 24, 27, 28].”
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- Authors
- Liu, H.-W., & Chang, S.-J.
- Affiliations
- National Taiwan Normal University (TW)
- National Cheng Kung University (TW)
- Corresponding author
- Liu, Hung-Wen
- ORCID
- Liu, Hung-Wen
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2018-05-29
- Volume
- 9
- Pages
- 636-636
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC5987703
- OpenAlex
- W2799744365
- Cited by
- 113
- References
- 34
- Citations by year
- 2026: 17 · 2025: 10 · 2024: 19 · 2023: 14 · 2022: 12 · 2021: 14 · 2020: 17 · 2019: 9 · 2018: 1
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Science and Technology (105-2410-H-003-151)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- moderate exercise training, type 2 diabetes, skeletal muscle atrophy, NF-κB signaling, SIRT1, AMPK, PGC-1α, mitochondrial biogenesis, mitochondrial dysfunction, db/db mice, MuRF1, K48-linked polyubiquitination, FOXO3, insulin resistance, muscle mass
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