Dataset Information

Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle Cell Line

SUBMITTER: JIMMY RODRIGUEZ

LAB HEAD: Hakan Westerblad

PROVIDER: PXD022997 | Pride | 2021-03-16

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20180312_02_Qp1_TMT_1_Maja.raw	Raw
	20180312_03_Qp1_TMT_2_Maja.raw	Raw
	Cluserproteomics.xlsx	Xlsx

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Publications

Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation.

Wyckelsma Victoria L VL Venckunas Tomas T Houweling Peter J PJ Schlittler Maja M Lauschke Volker M VM Tiong Chrystal F CF Wood Harrison D HD Ivarsson Niklas N Paulauskas Henrikas H Eimantas Nerijus N Andersson Daniel C DC North Kathryn N KN Brazaitis Marius M Westerblad Håkan H

American journal of human genetics 20210217 3

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 ...[more]

PMID: 33600773

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