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1.
Mamm Genome ; 34(2): 180-199, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37294348

RESUMO

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice.


Assuntos
Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Camundongos , Animais , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos
2.
Nat Commun ; 13(1): 6830, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369285

RESUMO

Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging.


Assuntos
Envelhecimento , Longevidade , Camundongos , Animais , Masculino , Longevidade/genética , Camundongos Endogâmicos C57BL , Envelhecimento/fisiologia , Fenótipo
3.
EMBO Mol Med ; 13(12): e14397, 2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34750991

RESUMO

Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh-/- ), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh-/- mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL ), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh-/- mouse is a valuable model for future studies of human CIII deficiency.


Assuntos
Doenças Mitocondriais , Animais , Complexo III da Cadeia de Transporte de Elétrons , Éxons , Homozigoto , Humanos , Camundongos , Doenças Mitocondriais/genética , Fenótipo , Deleção de Sequência
4.
Nat Commun ; 9(1): 288, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29348434

RESUMO

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.


Assuntos
Metabolismo Basal/genética , Glicemia/metabolismo , Peso Corporal/genética , Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Consumo de Oxigênio/genética , Triglicerídeos/metabolismo , Animais , Área Sob a Curva , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Ensaios de Triagem em Larga Escala , Humanos , Doenças Metabólicas/genética , Camundongos , Camundongos Knockout , Fenótipo
5.
J Am Assoc Lab Anim Sci ; 55(4): 375-86, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27423143

RESUMO

Although various mouse inbred strains are widely used to investigate disease mechanisms and to establish new therapeutic strategies, sex-specific reference intervals for laboratory diagnostic analytes that are generated from large numbers of animals have been unavailable. In this retrospective study, we screened data from more than 12,000 mice phenotyped in the German Mouse Clinic from January 2006 through June 2014 and selected animals with the genetic background of C57BL/6J, C57BL/6N, or C3HeB/FeJ. In addition, we distinguished between the C57BL/6NTac substrain and C57BL/6N mice received from other vendors. The corresponding data sets of electrolytes (sodium, potassium, calcium, chloride, inorganic phosphate), lipids (cholesterol, triglyceride), and enzyme activities (ALT, AST, ALP, α-amylase) and urea, albumin, and total protein levels were analyzed. Significant effects of age and sex on these analytes were identified, and strain- or substrain- and sex-specific reference intervals for 90- to 135-d-old mice were calculated. In addition, we include an overview of the literature that reports clinical chemistry values for wild-type mice of different strains. Our results support researchers interpreting clinical chemistry values from various mouse mutants and corresponding wild-type controls based on the examined strains and substrains.


Assuntos
Química Clínica/normas , Camundongos Endogâmicos C3H/fisiologia , Camundongos Endogâmicos C57BL/fisiologia , Animais , Feminino , Masculino , Camundongos , Fenótipo , Valores de Referência , Estudos Retrospectivos , Fatores Sexuais
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