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

ABSTRACT: 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.

SUBMITTER: Wyckelsma VL

PROVIDER: S-EPMC8008486 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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.

2021-03-16 | PXD022997 | Pride

Response to Wyckelsma et al.: Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation.

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.

| S-EPMC9118108 | biostudies-literature

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

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)

2021-01-16 | GSE164936 | GEO

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

Project description:Loss of a-actinin-3 during human evolution provides superior cold resilience and muscle heat generation

| PRJNA692479 | ENA

The structure and regulation of human muscle α-actinin.

Project description:The spectrin superfamily of proteins plays key roles in assembling the actin cytoskeleton in various cell types, crosslinks actin filaments, and acts as scaffolds for the assembly of large protein complexes involved in structural integrity and mechanosensation, as well as cell signaling. α-actinins in particular are the major actin crosslinkers in muscle Z-disks, focal adhesions, and actin stress fibers. We report a complete high-resolution structure of the 200 kDa α-actinin-2 dimer from striated muscle and explore its functional implications on the biochemical and cellular level. The structure provides insight into the phosphoinositide-based mechanism controlling its interaction with sarcomeric proteins such as titin, lays a foundation for studying the impact of pathogenic mutations at molecular resolution, and is likely to be broadly relevant for the regulation of spectrin-like proteins.

| S-EPMC4259493 | biostudies-literature

Alpha-actinin binding kinetics modulate cellular dynamics and force generation.

Project description:The actin cytoskeleton is a key element of cell structure and movement whose properties are determined by a host of accessory proteins. Actin cross-linking proteins create a connected network from individual actin filaments, and though the mechanical effects of cross-linker binding affinity on actin networks have been investigated in reconstituted systems, their impact on cellular forces is unknown. Here we show that the binding affinity of the actin cross-linker ?-actinin 4 (ACTN4) in cells modulates cytoplasmic mobility, cellular movement, and traction forces. Using fluorescence recovery after photobleaching, we show that an ACTN4 mutation that causes human kidney disease roughly triples the wild-type binding affinity of ACTN4 to F-actin in cells, increasing the dissociation time from 29 ± 13 to 86 ± 29 s. This increased affinity creates a less dynamic cytoplasm, as demonstrated by reduced intracellular microsphere movement, and an approximate halving of cell speed. Surprisingly, these less motile cells generate larger forces. Using traction force microscopy, we show that increased binding affinity of ACTN4 increases the average contractile stress (from 1.8 ± 0.7 to 4.7 ± 0.5 kPa), and the average strain energy (0.4 ± 0.2 to 2.1 ± 0.4 pJ). We speculate that these changes may be explained by an increased solid-like nature of the cytoskeleton, where myosin activity is more partitioned into tension and less is dissipated through filament sliding. These findings demonstrate the impact of cross-linker point mutations on cell dynamics and forces, and suggest mechanisms by which such physical defects lead to human disease.

| S-EPMC4450414 | biostudies-literature

Associations of the Alpha-Actinin Three Genotype with Bone and Muscle Mass Loss among Middle-Aged and Older Adults.

Project description:Bone and muscle mass loss are known to occur simultaneously. The alpha-actinin three (ACTN3) genotype has been shown to potentially affect bone and muscle mass. In this study, we investigated the association between the ACTN3 genotype and bone and muscle mass loss in community-dwelling adults aged ≥ 60 years. This study was a cross-sectional analysis of data from 295 participants who participated in a community health checkup. The ACTN3 genotypes were classified as RR, RX, or XX types. Bone mass loss was defined as a calcaneal speed of sound T-score of <−1.32 and <−1.37, and muscle mass loss was defined as an appendicular skeletal muscle index of <7.0 kg/m2 and <5.7 kg/m2 in men and women, respectively. The percentages of XX, RX, and RR in the combined bone and muscle mass loss group were 33.8%, 30.8%, and 16.7%, respectively, with a significantly higher trend for XX. Multinomial logistic regression analysis showed that XX had an odds ratio of 3.00 (95% confidence interval 1.05−8.54) of being in the combined bone and muscle mass loss group compared to the RR group (covariates: age, sex, grip strength, and medications). The ACTN3 genotype of XX is associated with a higher rate of comorbid bone and muscle mass loss. Therefore, ACTN3 genotyping should be considered for preventing combined bone and muscle mass loss.

| S-EPMC9605580 | biostudies-literature

Smooth muscle titin Zq domain interaction with the smooth muscle alpha-actinin central rod.

Project description:Actin-myosin II filament-based contractile structures in striated muscle, smooth muscle, and nonmuscle cells contain the actin filament-cross-linking protein alpha-actinin. In striated muscle Z-disks, alpha-actinin interacts with N-terminal domains of titin to provide a structural linkage crucial for the integrity of the sarcomere. We previously discovered a long titin isoform, originally smitin, hereafter sm-titin, in smooth muscle and demonstrated that native sm-titin interacts with C-terminal EF hand region and central rod R2-R3 spectrin-like repeat region sites in alpha-actinin. Reverse transcription-PCR analysis of RNA from human adult smooth muscles and cultured rat smooth muscle cells and Western blot analysis with a domain-specific antibody presented here revealed that sm-titin contains the titin gene-encoded Zq domain that may bind to the alpha-actinin R2-R3 central rod domain as well as Z-repeat domains that bind to the EF hand region. We investigated whether the sm-titin Zq domain binds to alpha-actinin R2 and R3 spectrin repeat-like domain loops that lie in proximity with two-fold symmetry on the surface of the central rod. Mutations in alpha-actinin R2 and R3 domain loop residues decreased interaction with expressed sm-titin Zq domain in glutathione S-transferase pull-down and solid phase binding assays. Alanine mutation of a region of the Zq domain with high propensity for alpha-helix formation decreased apparent Zq domain dimer formation and decreased Zq interaction with the alpha-actinin R2-R3 region in surface plasmon resonance assays. We present a model in which two sm-titin Zq domains interact with each other and with the two R2-R3 sites in the alpha-actinin central rod.

| S-EPMC2475687 | biostudies-literature

ClpG Provides Increased Heat Resistance by Acting as Superior Disaggregase.

Project description:Elevation of temperature within and above the physiological limit causes the unfolding and aggregation of cellular proteins, which can ultimately lead to cell death. Bacteria are therefore equipped with Hsp100 disaggregation machines that revert the aggregation process and reactivate proteins otherwise lost by aggregation. In Gram-negative bacteria, two disaggregation systems have been described: the widespread ClpB disaggregase, which requires cooperation with an Hsp70 chaperone, and the standalone ClpG disaggregase. ClpG co-exists with ClpB in selected bacteria and provides superior heat resistance. Here, we compared the activities of both disaggregases towards diverse model substrates aggregated in vitro and in vivo at different temperatures. We show that ClpG exhibits robust activity towards all disordered aggregates, whereas ClpB acts poorly on the protein aggregates formed at very high temperatures. Extreme temperatures are expected not only to cause extended protein unfolding, but also to result in an accelerated formation of protein aggregates with potentially altered chemical and physical parameters, including increased stability. We show that ClpG exerts higher threading forces as compared to ClpB, likely enabling ClpG to process "tight" aggregates formed during severe heat stress. This defines ClpG as a more powerful disaggregase and mechanistically explains how ClpG provides increased heat resistance.

| S-EPMC6995612 | biostudies-literature

Myozenin: an alpha-actinin- and gamma-filamin-binding protein of skeletal muscle Z lines.

Project description:To better understand the structure and function of Z lines, we used sarcomeric isoforms of alpha-actinin and gamma-filamin to screen a human skeletal muscle cDNA library for interacting proteins by using the yeast two-hybrid system. Here we describe myozenin (MYOZ), an alpha-actinin- and gamma-filamin-binding Z line protein expressed predominantly in skeletal muscle. Myozenin is predicted to be a 32-kDa, globular protein with a central glycine-rich domain flanked by alpha-helical regions with no strong homologies to any known genes. The MYOZ gene has six exons and maps to human chromosome 10q22.1-q22.2. Northern blot analysis demonstrated that this transcript is expressed primarily in skeletal muscle with significantly lower levels of expression in several other tissues. Antimyozenin antisera stain skeletal muscle in a sarcomeric pattern indistinguishable from that seen by using antibodies for alpha-actinin, and immunogold electron microscopy confirms localization specifically to Z lines. Thus, myozenin is a skeletal muscle Z line protein that may be a good candidate gene for limb-girdle muscular dystrophy or other neuromuscular disorders.

| S-EPMC29302 | biostudies-literature

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