| 1. |
- Aare, Sudhakar, et al.
(author)
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Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
- 2013
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In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 45:8, s. 312-320
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Journal article (peer-reviewed)abstract
- Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator, and a decreased quality of life post-ICU. The mechanisms underlying limb muscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization, and systemic administration of corticosteroids (CS). These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for 5 days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes according to microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional upregulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response, cytoskeletal, sarcomeric, and heat shock protein, as well as protein synthesis at the translational level, appears to play an additive deleterious role for the limb muscle weakness in immobilized ICU patients.
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| 2. |
- Aare, Sudhakar, et al.
(author)
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Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
- 2011
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 43:24, s. 1334-1350
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Journal article (peer-reviewed)abstract
- Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.
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| 3. |
- Aare, Sudhakar, et al.
(author)
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The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
- 2012
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 44:18, s. 865-877
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Journal article (peer-reviewed)abstract
- Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.
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| 4. |
- Albinsson, Sebastian, et al.
(author)
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Can microRNAs control vascular smooth muscle phenotypic modulation and the response to injury?
- 2010
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; okt
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Journal article (peer-reviewed)abstract
- Vascular smooth muscle cell (VSMC) migration and proliferation are critical events in vascular proliferative diseases. Recent studies have established micro-RNAs (miRNAs) as important mediators for the modulation of VSMC phenotype by targeting transcription factors and the cytoskeleton, which act as molecular switches for VSMC differentiation. The importance of miRNAs for VSMC development, differentiation and function is evident by the fact that loss of the miRNA processing enzyme Dicer in VSMCs results in embryonic lethality due to severe vascular abnormalities. In addition, a role of specific miRNAs for neointimal hyperplasia following vascular injury has been reported which provides interesting possibilities for future therapeutical targets against vascular disease. Herein, we summarize recent advances regarding the role of miRNAs in VSMC phenotype modulation and response to injury.
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| 5. |
- Asp, Julia, 1973, et al.
(author)
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Comparison of human cardiac gene expression profiles in paired samples of right atrium and left ventricle collected in vivo
- 2012
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 44:1, s. 89-98
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Journal article (peer-reviewed)abstract
- Studies of expressed genes in human heart provide insight into both physiological and pathophysiological mechanisms. This is of importance for extended understanding of cardiac function as well as development of new therapeutic drugs. Heart tissue for gene expression studies is generally hard to obtain, particularly from the ventricles. Since different parts of the heart have different functions, expression profiles should likely differ between these parts. The aim of the study was therefore to compare the global gene expression in cardiac tissue from the more accessible auricula of the right atrium to expression in tissue from the left ventricle. Tissue samples were collected from five men undergoing aortic valve replacement or coronary artery bypass grafting. Global gene expression analysis identified 542 genes as differentially expressed between the samples extracted from these two locations, corresponding to similar to 2% of the genes covered by the microarray; 416 genes were identified as abundantly expressed in right atrium, and 126 genes were abundantly expressed in left ventricle. Further analysis of the differentially expressed genes according to available annotations, information from curated pathways and known protein interactions, showed that genes with higher expression in the ventricle were mainly associated with contractile work of the heart. Transcription in biopsies from the auricula of the right atrium on the other hand indicated a wider area of functions, including immunity and defense. In conclusion, our results suggest that biopsies from the auricula of the right atrium may be suitable for various genetic studies, but not studies directly related to muscle work.
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| 6. |
- Banduseela, Varuna, et al.
(author)
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Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle
- 2013
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 45:12, s. 477-486
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Journal article (peer-reviewed)abstract
- Critical illness myopathy (CIM) is characterized by a preferential loss of the motor protein myosin, muscle wasting, and impaired muscle function in critically ill intensive care unit (ICU) patients. CIM is associated with severe morbidity and mortality and has a significant negative socioeconomic effect. Neuromuscular blocking agents, corticosteroids, sepsis, mechanical ventilation, and immobilization have been implicated as important risk factors, but the causal relationship between CIM and the risk factors has not been established. A porcine ICU model has been used to determine the immediate molecular and cellular cascades that may contribute to the pathogenesis prior to myosin loss and extensive muscle wasting. Expression profiles have been compared between pigs exposed to the ICU interventions, i.e., mechanically ventilated, sedated, and immobilized for 5 days, with pigs exposed to critical illness interventions, i.e., neuromuscular blocking agents, corticosteroids, and induced sepsis in addition to the ICU interventions for 5 days. Impaired autophagy as well as impaired chaperone expression and protein synthesis were observed in the skeletal muscle in response to critical illness interventions. A novel finding in this study is impaired core autophagy machinery in response to critical illness interventions, which when in concert with downregulated chaperone expression and protein synthesis may collectively affect the proteostasis in skeletal muscle and may exacerbate the disease progression in CIM.
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| 7. |
- Chaillou, Thomas, 1985-, et al.
(author)
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Pitfalls in target mRNA quantification for real-time quantitative RT-PCR in overload-induced skeletal muscle hypertrophy
- 2011
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In: Physiological Genomics. - Bethesda, USA : American Physiological Society. - 1094-8341 .- 1531-2267. ; 43:4, s. 228-235
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Journal article (peer-reviewed)abstract
- Quantifying target mRNA using real-time quantitative reverse transcription-polymerase chain reaction requires an accurate normalization method. Determination of normalization factors (NFs) based on validated reference genes according to their relative stability is currently the best standard method in most usual situations. This method controls for technical errors, but its physiological relevance requires constant NF values for a fixed weight of tissue. In the functional overload model, the increase in the total RNA concentration must be considered in determining the NF values. Here, we pointed out a limitation of the classical geNorm-derived normalization. geNorm software selected reference genes despite that the NF values extensively varied under experiment. Only the NF values calculated from four intentionally selected genes were constant between groups. However, a normalization based on these genes is questionable. Indeed, three out of four genes belong to the same functional class (negative regulator of muscle mass), and their use is physiological nonsense in a hypertrophic model. Thus, we proposed guidelines for optimizing target mRNA normalization and quantification, useful in models of muscle mass modulation. In our study, the normalization method by multiple reference genes was not appropriate to compare target mRNA levels between overloaded and control muscles. A solution should be to use an absolute quantification of target mRNAs per unit weight of tissue, without any internal normalization. Even if the technical variations will stay present as a part of the intergroup variations, leading to less statistical power, we consider this method acceptable because it will not generate misleading results.
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| 8. |
- Ek, Weronica, et al.
(author)
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Genetic analysis of metabolic traits in an intercross between body weight-selected chicken lines
- 2010
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 42:1, s. 20-22
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Journal article (peer-reviewed)abstract
- A network of four interacting loci has been reported previously to influence growth in two lines of chickens divergently selected for body weight at 56 days of age. Located on chromosomes 3 (Growth4), 4 (Growth6), 7 (Growth9), and 20 (Growth12), they explained nearly half of the difference in body weight at selection age between the two lines. The original study reported effects on body weight and fat deposition, but no attempts were made to explore the effects of the network on other phenotypes measured in the F(2) population. In this study we conducted further analyses to evaluate the specific effects of the four-locus network on other metabolic traits as well as refining results from the original study by including a larger number of genetic markers in the quantitative trait locus (QTL) regions. We confirm the previously described effect of the epistatic network on body weight and show that the network increases the total amount of muscle and fat as well as the weight of the internal organs. The network as a whole did not change the relative content of any studied organs or tissues in the body. There was, however, a significant interaction between the loci on chromosomes 3 and 7 that changed the relative proportion of abdominal fat and breast muscle in the chicken by increasing abdominal fat weight without a corresponding increase in muscle mass.
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| 9. |
- Geahlen, J. H., et al.
(author)
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Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3
- 2013
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 45:15, s. 667-683
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Journal article (peer-reviewed)abstract
- In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.
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| 10. |
- Gomez-Gallego, F, et al.
(author)
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Are elite endurance athletes genetically predisposed to lower disease risk?
- 2010
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In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 41:1, s. 82-90
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Journal article (peer-reviewed)abstract
- We compared a polygenic profile that combined 33 disease risk-related mutations and polymorphisms among nonathletic healthy control subjects and elite endurance athletes. The study sample comprised 100 healthy Spanish male nonathletic (sedentary) control subjects and 100 male elite endurance athletes. We analyzed 33 disease risk-related mutations and polymorphisms. We computed a health-related total genotype score (TGS, 0–100) from the accumulated combination of the 33 variants. We did not observe significant differences in genotype or allele distributions among groups, except for the rs4994 polymorphism ( P < 0.001). The computed health-related TGS was similar among groups (23.8 ± 1.0 vs. 24.2 ± 0.8 in control subjects and athletes, respectively; P = 0.553). Similar results were obtained when computing specific TGSs for each main disease category (cardiovascular disease and cancer). We observed no evidence that male elite endurance athletes are genetically predisposed to have lower disease risk than matched nonathletic control subjects.
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