Loss of a-actinin-3 during human evolution provides superior cold resilience and muscle heat generation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA692479 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13446200_1.fastq.gz | Fastqsanger.gz | |||
| SRR13446200_2.fastq.gz | Fastqsanger.gz | |||
| SRR13446201_1.fastq.gz | Fastqsanger.gz | |||
| SRR13446201_2.fastq.gz | Fastqsanger.gz | |||
| SRR13446202_1.fastq.gz | Fastqsanger.gz |
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Project description:The fast skeletal muscle protein α-actinin-3 is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in the ACTN3 gene (R577X). The prevalence of the 577X allele increased as modern humans moved to colder climates, suggesting a link between α-actinin-3 deficiency and improved cold tolerance. Here, we show that humans lacking α-actinin-3 (XX) are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. Muscles of XX individuals displayed a shift towards more slow-twitch isoforms of myosin heavy chain (MyHC) and sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal muscle activation resulting in increased tone rather than overt shivering. Experiments on Actn3 knockout mice showed no alterations in brown adipose tissue (BAT) properties that could explain the improved cold tolerance in XX individuals. Thus, this study provides a clear mechanism for the positive selection of the ACTN3 X-allele in cold climates and supports a key thermogenic role of skeletal muscle during cold exposure in humans.
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Project description:To examine if the loss of alpha-actinin-3, a fast skeletal muscle protein, modifies core body temperture following acute cold exposure in humans and a mice Using an Actn3 KO mice model we explore the effects of cold exposure on brown adipose tissue function following exposure to cold (4oC) for 5 hours, compared to control mice housed at either thermoneutrality (30oC) or standard room temperature (22oC)
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Project description:The protein α-actinin-3 expressed in fast-twitch skeletal muscle fiber is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in ACTN3 (R577X). The prevalence of the 577X allele increased as modern humans moved to colder climates, suggesting a link between α-actinin-3 deficiency and improved cold tolerance. Here, we show that humans lacking α-actinin-3 (XX) are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. Muscles of XX individuals displayed a shift toward more slow-twitch isoforms of myosin heavy chain (MyHC) and sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal muscle activation resulting in increased tone rather than overt shivering. Experiments on Actn3 knockout mice showed no alterations in brown adipose tissue (BAT) properties that could explain the improved cold tolerance in XX individuals. Thus, this study provides a mechanism for the positive selection of the ACTN3 X-allele in cold climates and supports a key thermogenic role of skeletal muscle during cold exposure in humans.
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Project description:The RANBP2/Importin-7-FOXO1 axis provides superior cold protection to aid islet transplantation
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Project description:The common loss-of-function mutation R577X in the structural muscle protein ACTN3 emerged as a potential target of positive selection from early studies and has been the focus of insightful physiological work suggesting a significant impact on muscle metabolism. Adaptation to cold climates has been proposed as a key adaptive mechanism explaining its global allele frequency patterns. Here, we re-examine this hypothesis analyzing modern (n = 3,626) and ancient (n = 1,651) genomic data by using allele-frequency as well as haplotype homozygosity-based methods. The presented results are more consistent with genetic drift rather than selection in cold climates as the main driver of the ACTN3 R577X frequency distribution in human populations across the world. This Matters Arising paper is in response to Wyckelsma et al. (2021),1 published in The American Journal of Human Genetics. See also the response by Wyckelsma et al. (2022),2 published in this issue.
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Project description:Potato seedlings were subjected to cold, heat and salt stress. Expression profiles were captured at three different time-points, 3h, 9h and 27h from two different tissues, roots and leaves. The experiment was preformed independently three times. Commercially available true potato seeds (Variety Gilroy) were germinated on rafts floating on hydroponic medium in Magenta boxes. Plants were grown for 5 weeks prior to stress application under long day conditions (16h light and 8h dark) at 25C with gentle agitation. To initiate stress the medium was replaced with fresh medium pre-chilled to 4C (cold stress), pre-heated to 35C (heat stress) or supplemented with 100mM NaCl (salt stress). Cold and heat stress were maintained for the duration of the experiment by placing the Magenta boxes on ice or in a water-bath at 35C. For every individual sample two boxes of plants were used pooling a total of 6 plants per sample. For each time-point a single control sample was used by changing the media in a similar way as for the stress induction. A total of six boxes were combined for the pooled reference samples. Plants were harvested at the appropriate time and snap-frozen in liquid nitrogen. Roots and aerial tissue was separated prior to freezing. The tissue was stored at -80C freezer until isolation. Total RNA was isolated using RNeasy isolation kit. The intactness of the RNA was verified on gel and the concentration was adjusted to 3ug/ul by ethanol precipitation and re-suspension. Series_weblink: http://www.tigr.org/tdb/potato Keywords = potato, Abiotic stress
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