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Statistical Considerations and Biological Mechanisms Underlying Individual Differences in Adaptations to Exercise Training
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Jacob T. Bonafiglia, Hashim Islam, Nir Eynon, Brendon J. Gurd
A limitation of studying single genetic variants is the inherent complexity of the adaptive response to exercise—a complexity that reflects combined contributions from multiple genetic variants (i.e., polygenic) (72, 86). Cognizant of this genetic complexity, Bouchard and colleagues re-analysed samples from the HERITAGE study using combined association scores across multiple variants (20). Specifically, they conducted a GWAS examining over 324,000 single nucleotide polymorphisms (SNPs) and identified 39 SNPs that were significantly (p < 1.5 ×10−4) associated with changes in VO2 max (20). Multivariate regression analysis found that the combined effects of 21 of these SNPs accounted for ∼49% of the variance in observed VO2 max responses—an effect size that is similar to the heritability estimate (∼47%) derived from the familial aggregation analysis reported in 1999 (18). Importantly, these 21 SNPs accounted for a larger amount of variance in observed VO2 max responses compared to the strongest individual variant (only ∼7% of variance explained by ACSL1), thus highlighting the strength of multivariate polygenic approaches. Bouchard and colleagues also created “predictor scores” based on zygosity for each of the 21 SNPs, and these scores effectively separated high and low VO2 max responses (20). Evidently, findings from the HERITAGE Family Study suggest that genetics contributes to variability in VO2 max response and support the notion that low and high VO2 max responders exhibit divergent genetic profiles (82). However, these data should be looked at with caution, since many of these identified SNPs have not been replicated (86) and the statistical threshold chosen was low compared to other GWAS studies.
Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
An analysis of miRNA expression profiles between old and young murine liver specimens revealed four miRNAs upregulated with aging, miR-669c (9.9-fold upregulation in 33-month-old mice compared with 4-month-old ones), miR-709 (7.6-fold), miR-214 (3.4-fold), and miR-93 (4.3-fold) [84]. Only miR-669c and miR-709 showed a gradual increase with age, whereas miR-93 and miR-214 showed biphasic expression at 10- and 18–33-month ages. Several miRNAs were found to decrease at 33 months compared with 10 months (miR-375, let-7i and let-7g). At least 24% of proteins significantly downregulated at 33 months appeared to be targets of the four upregulated miRNAs. Importantly, several of these proteins (Acsl1, Gstz1, Uqcrc1, and Mgst1) are linked with mitochondria. Several downregulated glutathione S-transferases are also among the predicted targets. Obviously, these miRNAs may be implicated in an aging mechanism related to oxidative stress. Specifically, a decline in oxidative protection is correlated with miR-93 targeted Mgst1, and the failure of the mitochondrial respiratory chain is correlated with miR-709 targeted Uqcrc1. Insulin-like growth factor 1 (Igf1) is among the predicted targets of miR-93; it may have a role in the IIS pathway similar to lin-4 in C. elegans. Decreased IIS pathway activity is intrinsically related to conditions of CR and may influence longevity. The gene for miR-669c is located in an intron of the gene encoding Sfmbt2, a Polycomb group (PcG) protein, known to functionally interact with TF Yinyang1 (YY1), possibly forming a PcG silencing complex [85]. The gene for miR-709 is found in an intron of the gene encoding TF Rfx1, a known activator of the virus gene expression and suppressor of cellular genes, such as c-myc and PCNA. One of the miR-709 targets is Brother of the Regulator of Imprinted Sites (BORIS), known to play an important role in epigenetic reprogramming during the male germ cell differentiation [86]. Its downregulation by miR-709 may be the cause of age-dependent decline in spermatogenesis.
Dietary S. maltophilia induces supersized lipid droplets by enhancing lipogenesis and ER-LD contacts in C. elegans
Published in Gut Microbes, 2022
Kang Xie, Yangli Liu, Xixia Li, Hong Zhang, Shuyan Zhang, Ho Yi Mak, Pingsheng Liu
A forward genetic screen was conducted to identify C. elegans host factors that mediate the S. maltophilia effect on LDs. We used DHS-3::GFP or MDT-28::mCherry as LD markers (Fig. 4a and 4b) and screened 7,000 haploid genomes after chemical mutagenesis with ethyl-methane sulfonate (EMS), and isolated 7 mutant strains (Figure 4a). Genetic mapping based on single nucleotide polymorphisms (SNPs) eventually led to the molecular cloning of two genes: acs-13 and dpy-9 (Figure 4c-Figure 4h). The acs-13 gene encodes an ortholog of human ACSL1, 5, 6 (acyl-CoA synthetase long-chain family member 1, 5, 6). The dpy-9 gene encodes a cuticular collagen family member with similarity to human collagen alpha 5, type IV. Using complementation tests and RNAi, we confirmed that the loss of acs-13 and dpy-9 function blocked the ability of S. maltophilia to induce LD expansion in C. elegans (Figure 4a-4h).
Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy
Published in Journal of Drug Targeting, 2022
Gang Wang, Jun-Jie Wang, Xiao-Na Xu, Feng Shi, Xing-Li Fu
Fatty acid metabolic enzymes are related to the prognosis and progression of several cancers, including colorectal cancer [40,41]. Notably, acyl CoA synthetase (ACSL) expression and clinical outcomes indicate that ACSL1, which is used more for triglyceride synthesis [42], is upregulation in CRC [43]. Acylcarnitines are generated through the transfer of carnitine for CoA on acyl-CoA derivatives of long-chain FA by carnitine palmitoyltransferase (CPT), to transport them through the mitochondrial membrane [44]. Thus, elevated acylcarnitine levels can be due to increased CPT activity resulting from an increase in the cytoplasmic acyl-CoA substrate levels, such as the ACSL1 products. Regarding glycolytic perturbations, increased phosphoenolpyruvate (PEP) levels and normal pyruvate could be a reflection of less of a demand of TCA feeding from pyruvate (from carbohydrates) explaining a lower basal oxygen consumption rate (OCR), since a more energetic status is achieved through other alternative supplies, such as FAO, that could be fed by ACSL1 overexpression [45]. For instance, the FAO inhibitor etomoxir is insufficient for reversing the EMT phenotype of ACSL/SCD cells that, conversely, can be achieved upon a more drastic energetic restriction caused by the reactivation of AMP-activated protein kinase (AMPK) signalling upon metformin treatment [46].
The inhibition of Nrf2 accelerates renal lipid deposition through suppressing the ACSL1 expression in obesity-related nephropathy
Published in Renal Failure, 2019
Yinyin Chen, Liyu He, Yiya Yang, Ying Chen, Yanran Song, Xi Lu, Yumei Liang
Schneider et al. [8] has been demonstrated that fatty acid transport and uptake disorder in kidney is highly relevant for the renal lipid deposition. Renal lipid deposition is a crucial pathological change in ORN and inhibiting renal lipid deposition could slow the progression of ORN [9]. Storage of fatty acid as triglyceride (TG) requires the activation of fatty acids to long-chain acyl-CoAs (LC-CoA) by the enzyme acyl-CoA synthetase (ACSL). There are five known isoforms of ACSL (ACSL1, −3, −4, −5, −6), which vary in their tissue specificity and affinity for fatty acid substrates [10]. Long chain acyl-CoA synthetases-1, (ACSL1), is a key enzyme in the oxidative metabolism of fatty acids in mitochondria. ACSL1 not only could activate fatty acids for intracellular metabolism but are also involved in the regulation of uptake [11]. ACSL1 has been reported in fatty liver, skeletal muscle lipid degeneration, and ACSL is involved in lipid metabolism in different cells, either increasing lipid deposition or promoting lipid catabolism [12,13]. In kidney, inhibition of ASCL1 would result lipotoxic, finally expediting proximal tubule apoptosis [3,9]. Based on these data, we believe ACSL1 may be a key role in the progression of ORN. Interestingly, recent studies have emphasized the association of oxidative stress (ROS) with the pathogenesis of metabolic disorders in obesity [14]. ROS production was thought to be key importance in obesity-related kidney disease [15]. In addition, Trindade de Paula et al. confirmed that ROS levels were opposite to ACSL1 levels [16]. So, ROS production may be involved in the ORN through inhibiting the ACSL1 expression.