ECSS Paris 2023: OP-PN26
INTRODUCTION: Adipose tissue fibrosis is a crucial pathological feature of age-related functional decline in adipose tissue, which can exacerbate metabolic disorders and promote systemic aging. Using the senescence-accelerated mouse model SAMP8, this study first aimed to identify the critical time points for adipose tissue aging and fibrosis development and screen for underlying molecular mechanisms at the transcriptomic level. Furthermore, it investigated the interventional effects of moderate-intensity aerobic exercise on subcutaneous adipose tissue fibrosis during aging and the potential signaling pathways involved, providing experimental evidence for exercise in delaying adipose tissue aging and associated fibrosis. METHODS: During the aging process of SAMP8 male mice, the senescence score, body weight and relative weight of subcutaneous adipose tissue were measured at 2, 4, 6, 8, 10 and 12 months of age. Subcutaneous adipose tissues pf each age were collected for aging, fibrosis phenotype detected. Transcriptome sequencing, time-series clustering, and KEGG pathway enrichment analysis were conducted on subcutaneous adipose tissue from 2-, 8-, and 12-month-old mice. Then 2, 7-month-old male SAMP8 mice were randomly assigned to a sedentary control group (Con) or an aerobic exercise group (Ex), undergoing 8 weeks of moderate-intensity treadmill training(MICT). Differences between groups were compared regarding body weight, relative subcutaneous adipose tissue weight, senescence and fibrosis phenotypes, and the mRNA and protein expression of Neu1/ALK5-Smad2/3 pathway components. RESULTS: Compared to the 2-month group, 8-month groups showed significantly increased senescence scores (P<0.01), higher positive rates of p16 and p21 in subcutaneous adipose tissue (P<0.01), aggravated collagen fiber deposition (P<0.01), upregulated mRNA expression of Sma, Col6α1, and Timp1 (P<0.05) , downregulated Mmp9 expression (P<0.05). Transcriptome sequencing and time-series clustering analysis showed that the C4 gene cluster expression continuously increased with age, with the sialidase-encoding gene Neu1 significantly highly expressed at 8 and 12 months. After 8-weeks MICT, the relative weight of subcutaneous adipose tissue, the positive expression rates of p16 and p21, and the area of collagen deposition in the mice of the exercise group were significantly reduced (P < 0.05). The expressions of fibrosis-related genes Sma and Col6α1 were significantly downregulated (P < 0.05), the expression of Mmp9 was significantly upregulated (P < 0.05), and the mRNA expressions of Neu1, Tgfbr1, and the protein expressions of NEU1, ALK5, and p-Smad2 were all significantly decreased (P < 0.05). CONCLUSION: 8-months is the key time point for the occurrence and development of age-related fibrosis in adipose tissue. 8-weeks MICT can effectively delay the process of fat aging by down-regulating the expression level of the NEU1/ALK5-Smad2/3 pathway in subcutaneous adipose tissue.
Read CV YI YANECSS Paris 2023: OP-PN26
INTRODUCTION: Metabolic-associated fatty liver disease (MAFLD) is often accompanied by the abnormal activation of hepatic pyroptosis. Gasdermin D (GSDMD)-mediated mitochondrial and cell membrane pore formation is the core mechanism regulating hepatic pyroptosis, and play a critical role in the pathophysiology of this disease. This study aimed to investigate the effects of exercise intervention on mitochondrial damage-mediated hepatic pyroptosis in MAFLD rats. METHODS: Fifty-six SD rats were randomly divided into three groups (n=14 each): normal control (NC), HFFC model (HC), and HFFC + exercise (HE), with an 8-week intervention. At the end, body and liver weights were measured. Blood samples were collected to detect serum ALT, AST, CHOL, TG, IL-18, and IL-1β. Liver tissue was homogenized to extract mitochondria and cytoplasm. Mitochondrial function was detected, and cytoplasm was used for 8-OHG detection. Frozen liver sections were subjected to immunofluorescence staining for GSDMD colocalization with WGA and TOM20. RESULTS: 1)Compared with the NC group, the HC group showed a significant increase in body weight (+18.38%), liver index (+114.77%), and serum levels of ALT (+171.93%), AST (+220.08%), CHOL (+109.09%), and TG (+76.6%). In contrast, the HE group exhibited a significant decrease in the above indices compared with the HC group, with body weight (-9.22%), liver index (-26.24%), ALT (-37.26%), AST (-46.8%), CHOL (-44.16%), and TG (-39.02%) all reduced significantly (P<0.05). 2)Serum levels of IL-18 (24.07±2.32 vs 53.64±3.66 pg/mL), IL-1β (34.87±2.96 vs 93.68±5.06 pg/mL), and cytoplasmic 8-OHG level (2.31±0.20 vs 4.55±0.43) were significantly higher in the HC group than in the NC group, while these indices were markedly decreased in the HE group (IL-18: 23.97±2.70 pg/mL; IL-1β: 51.96±10.97 pg/mL; 8-OHG: 2.62±0.48) compared with the HC group (P<0.05). 3)The mitochondrial mitochondrial respiratory control ratio (RCR) respiratory control ratio value was significantly lower in the HC group than in the NC group (5.53±1.73 vs 3.82±0.87), whereas the colocalized positive areas of GSDMD with WGA (+75%) and GSDMD with TOM20 (+65.92%) were significantly increased. Compared with the HC group, the HE group had a significantly elevated of mitochondrial RCR (12.25±3.44) and a notable reduction in the colocalized positive areas of GSDMD with WGA (-30.15%) and GSDMD with TOM20 (-35.34%) (P<0.05). CONCLUSION: 1)HFFC diet induces significant hepatic lipid accumulation and dyslipidemia, impairs mitochondrial respiratory function, and promotes mitochondrial damege-mediated membrane pore formation, thereby triggering hepatocyte pyroptosis. 2)Exercise intervention effectively alleviates hepatic lipid deposition and dyslipidemia, enhances mitochondrial function, and suppresses mitochondrial and cellular GSDMD pore formation, consequently mitigating mitochondrial mediated pyroptosis and exerting a protective effect against MAFLD.
Read CV Yifan YaoECSS Paris 2023: OP-PN26
INTRODUCTION: Alzheimer’s disease (AD) is a neurodegenerative disorder and the leading cause of dementia, characterized by cognitive decline and neuronal and vascular dysfunction. AD is also recognized as a systemic condition associated with metabolic alterations, mitochondrial dysfunction, and redox imbalance in peripheral tissues including skeletal muscle. Postmenopausal women face a higher risk of AD driven by a combination of factors that may contribute to disease vulnerability and progression. Aerobic training (AT) has beneficial effects on these factors and may interfere with the progression of AD. In this study, we investigated the neuroprotective effects of AT in female APP/PS1 mice, a well stablished AD model, focusing on locomotor activity, cognition, anxiety- and depression-like behaviors, and hippocampal Aβ plaques, neuroinflammation, and vascularization. We also assessed whether AT modulates muscle oxidative stress in the gastrocnemius. METHODS: Six-month-old female APP/PS1 mice and wild-type (WT) controls were assigned to four groups (WT sedentary n=18; WT trained n=14; APP/PS1 sedentary n=11; APP/PS1 trained n=15). The trained groups underwent eight weeks of AT in treadmill. After the training program, locomotor activity, learning and memory, and anxiety- and depression-like behaviors were tested. Hippocampal immunohistochemistry was used to quantify Aβ plaques (6E10), microglia (Iba-1), astrocytes (GFAP), and vascular marker (tomato lectin). In the gastrocnemius, oxidative stress markers were quantified, including TBARS, protein carbonyls, hydrogen peroxide, and NADPH oxidase activity, as well as antioxidant defenses (SOD, GPx, and FRAP). RESULTS: AT rescued deficits in learning and memory (p<0.001), also produced anxiolytic (p<.001) and antidepressant-like effects (p<0.001) in APP/PS1 mice. In the hippocampus, AT decreased Iba-1 and GFAP immunoreactivity (p<0.001 and p=0.003 respectively). In addition, AT restored hippocampal vascularization in APP/PS1 mice to WT-like levels (p<0.001). These cognitive and tissue-level improvements occurred without a significant reduction in Aβ plaque deposition. At the peripheral level, AT improved muscle oxidative stress in APP/PS1 mice, SOD activity was reduced in sedentary groups and was restored in APP/PS1 trained to levels comparable to WT (carbonyls p<0.001 and SOD activity p=0.008), whereas other markers did not differ among groups. CONCLUSION: In female APP/PS1 mice, AT produced behavioral benefits, decreased neuroinflammatory markers and improved hippocampal vascularization. Moreover, AT improved muscle redox status and rescued a key antioxidant defense. Collectively, these findings indicate that aerobic exercise promotes central and peripheral resilience in female mice committed with AD.
Read CV Sthefanie OtavianoECSS Paris 2023: OP-PN26