| First Author | Wyckelsma VL | Year | 2021 |
| Journal | Am J Hum Genet | Volume | 108 |
| Issue | 3 | Pages | 446-457 |
| PubMed ID | 33600773 | Mgi Jnum | J:303994 |
| Mgi Id | MGI:6693873 | Doi | 10.1016/j.ajhg.2021.01.013 |
| Citation | Wyckelsma VL, et al. (2021) Loss of alpha-actinin-3 during human evolution provides superior cold resilience and muscle heat generation. Am J Hum Genet 108(3):446-457 |
| abstractText | The protein alpha-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 alpha-actinin-3 deficiency and improved cold tolerance. Here, we show that humans lacking alpha-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. |
