Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail

Petrocelli, Jonathan J; Hart, Naomi M.M.P. de; Lang, Marisa J; Yee, Elena M.; Ferrara, Patrick J.; Fix, Dennis K.; Chaix, Amandine; Funai, Katsuhiko; Drummond, Micah J.

doi:10.18632/aging.204600

Cited by 3 publications

(1 citation statement)

References 36 publications

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“…Aspirin, a cyclooxygenase inhibitor mainly used as an antiplatelet drug, reduces cell viability and decreases the levels of Bcl-xL protein in senescent fibroblast [ 28 ]. Metformin, a cost-effective and safe biguanide derivative used for the treatment of type 2 diabetes, and FK-506 or tacrolimus, a calcineurin inhibitor, were described as senomorphic drugs due to their ability to control SASP or improve the lifespan of senescent cells, respectively [ 29 , 30 ]. Therefore, azithromycin, rapamycin, aspirin, metformin, and FK-506, in addition to dasatinib, were combined with nine natural polyphenols.…”

Section: Introductionmentioning

confidence: 99%

Researching New Drug Combinations with Senolytic Activity Using Senescent Human Lung Fibroblasts MRC-5 Cell Line

de Godoy,

Macedo,

Gambero

2024

Pharmaceuticals

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Therapeutically targeting senescent cells seems to be an interesting perspective in treating chronic lung diseases, which are often associated with human aging. The combination of the drug dasatinib and the polyphenol quercetin is used in clinical trials as a senolytic, and the first results point to the relief of physical dysfunction in patients with idiopathic pulmonary fibrosis. In this work, we tested new combinations of drugs and polyphenols, looking for senolytic activity using human lung fibroblasts (MRC-5 cell line) with induced senescence. We researched drugs, such as azithromycin, rapamycin, metformin, FK-506, aspirin, and dasatinib combined with nine natural polyphenols, namely caffeic acid, chlorogenic acid, ellagic acid, ferulic acid, gallic acid, epicatechin, hesperidin, quercetin, and resveratrol. We found new effective senolytic combinations with dasatinib and ellagic acid and dasatinib and resveratrol. Both drug combinations increased apoptosis, reduced BCL-2 expression, and increased caspase activity in senescent MRC-5 cells. Ellagic acid senolytic activity was more potent than quercetin, and resveratrol counteracted inflammatory cytokine release during senolysis in vitro. In conclusion, dasatinib and ellagic acid and dasatinib and resveratrol present in vitro senolytic potential like that observed for the combination in clinical trials of dasatinib and quercetin, and maybe they could be future alternatives in the senotherapeutic field.

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Section: Introductionmentioning

confidence: 99%

Researching New Drug Combinations with Senolytic Activity Using Senescent Human Lung Fibroblasts MRC-5 Cell Line

de Godoy,

Macedo,

Gambero

2024

Pharmaceuticals

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Disuse‐induced muscle fibrosis, cellular senescence, and senescence‐associated secretory phenotype in older adults are alleviated during re‐ambulation with metformin pre‐treatment

et al. 2023

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Muscle inflammation and fibrosis underlie disuse‐related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re‐ambulation period. A two‐arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two‐week run‐in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin‐treated individuals had less type‐I myofiber atrophy during disuse, reduced pro‐inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro‐adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast‐like. Together, these results suggest that metformin pre‐treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs.

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GW8510 alleviated muscle atrophy and skeletal muscle dysfunction in mice through AMPK/PGC1α signaling

Chen,

Liu,

Liu

et al. 2024

Preprint

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Background To prevent and restore muscle loss and function is important for elderly people. Here, we explore the protective effect of GW8510 on muscle atrophy. Methods The denervation, dexamethasone, and glycerol-induced muscle atrophy mice were constructed and the ratio of muscle weight to body weight, the cross-sectional area of multiple muscles, grip strength, fatigue task, and serum analysis were assessed. In Vitro experiment, we constructed dexamethasone-induced C2C12 myotube atrophy and evaluated the mitochondrial function. Moreover, we applied real-time polymerase chain reaction, immunoblotting, and transfection with siRNA to investigate the potential molecular mechanism after GW8510 treatment. Results GW8510 significantly increases the ratio of gastrocnemius tissue and soleus in denervation mice (6.8% and 3.1%, respectively, P < 0.001), and increased cross-sectional area. Meanwhile, GW8510 significantly improved grip strength and SOD activity (P < 0.0001), and these protective effects were also found similarly in dexamethasone and glycerol-induced muscle atrophy mice. Furthermore, GW8510 reduced reactive oxygen species production (P < 0.01), increased mitochondrial DNA copy number (P < 0.01), maintained mitochondrial dynamics, and enhanced the antioxidation in C2C12 myotubes. Mechanistically, GW8510 significantly inhibited the expression of atrophy-related markers, Fbxo32 and Trim63 (P < 0.01 and activated AMPK (P < 0.01). Knockdown of small interfering RNA abolished the effect of GW8510 and knockdown of Src synergistically reduced atrophy-related protein. Conclusion GW8510 alleviated muscle atrophy through activation of AMPK/ PGC1α. Our study identified that GW8510 can be a novel therapeutical agent for preventing muscle atrophy, and Src may be a novel therapeutical target.

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Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail

Cited by 3 publications

References 36 publications

Researching New Drug Combinations with Senolytic Activity Using Senescent Human Lung Fibroblasts MRC-5 Cell Line

Researching New Drug Combinations with Senolytic Activity Using Senescent Human Lung Fibroblasts MRC-5 Cell Line

Disuse‐induced muscle fibrosis, cellular senescence, and senescence‐associated secretory phenotype in older adults are alleviated during re‐ambulation with metformin pre‐treatment

GW8510 alleviated muscle atrophy and skeletal muscle dysfunction in mice through AMPK/PGC1α signaling

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