Validation of positional candidates Rps6ka6 and Pou3f4 for a locus associated with skeletal muscle mass variability
Year: 2024
Type: article
Abstract: Genetic variability significantly contributes to individual differences in skeletal muscle mass; however, the specific genes involved in that process remain elusive. In this study, we examined the role of positional candidates, Rps6ka6 and Pou3f4, of a chromosome X locus, implicated in muscle mass variability in CFW laboratory mice. Histology of hindlimb muscles was studied in CFW male mice carrying the muscle "increasing" allele C (n = 15) or "decreasing" allele T (n = 15) at the peak marker of the locus, rs31308852, and in the Pou3f4y/- and their wild-type male littermates. To study the role of the Rps6ka6 gene, we deleted exon 7 (Rps6ka6-ΔE7) using clustered regularly interspaced palindromic repeats-Cas9 based method in H2Kb myogenic cells creating a severely truncated RSK4 protein. We then tested whether that mutation affected myoblast proliferation, migration, and/or differentiation. The extensor digitorum longus muscle was 7% larger (P < 0.0001) due to 10% more muscle fibers (P = 0.0176) in the carriers of the "increasing" compared with the "decreasing" CFW allele. The number of fibers was reduced by 15% (P = 0.0268) in the slow-twitch soleus but not in the fast-twitch extensor digitorum longus (P = 0.2947) of Pou3f4y/- mice. The proliferation and migration did not differ between the Rps6ka6-ΔE7 and wild-type H2Kb myoblasts. However, indices of differentiation (myosin expression, P < 0.0001; size of myosin-expressing cells, P < 0.0001; and fusion index, P = 0.0013) were significantly reduced in Rps6ka6-ΔE7 cells. This study suggests that the effect of the X chromosome locus on muscle fiber numbers in the fast-twitch extensor digitorum longus is mediated by the Rps6ka6 gene, whereas the Pou3f4 gene affects fiber number in slow-twitch soleus.
Source: G3 Genes Genomes Genetics
Authors: Konstantinos Lekkos, Afra A Bhuiyan, Abdullah M K Albloshi, Paige M Brooks, Thomas M Coate, Arimantas Lionikas
Institutions: University of Aberdeen, Georgetown University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,790
Funders: Wellcome Trust, Chief Scientist Office, University of Aberdeen, National Institutes of Health, National Institute on Deafness and Other Communication Disorders, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences, FP7 People: Marie-Curie Actions
Awards: Translational Biomedical Science Training Grant, G2203337149, G2911823071, G2985861801, G3303985150, Dissection of Muscle Weight QTL Via Congenic Strains, Institutional Strategic Support Fund, Pou3f4-expressing Otic Mesenchyme Cells: A Novel Influence for Spiral Ganglion Neuron Survival, Genetic Variation of Muscle Mass, Cellular and Molecular Mechanisms of Cochlear Innervation
OpenAlex ID: W4393992166