PMID- 35081669 OWN - NLM STAT- MEDLINE DCOM- 20220405 LR - 20220731 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 600 IP - 7 DP - 2022 Apr TI - KLB dysregulation mediates disrupted muscle development in intrauterine growth restriction. PG - 1771-1790 LID - 10.1113/JP281647 [doi] AB - Intrauterine growth restriction (IUGR) is a leading cause of neonatal morbidity and mortality in humans and domestic animals. Developmental adaptations of skeletal muscle in IUGR lead to increased risk of premature muscle loss and metabolic disease in later life. Here, we identified beta-Klotho (KLB), a fibroblast growth factor 21 (FGF21) co-receptor, as a novel regulator of muscle development in IUGR. Using the pig as a naturally-occurring disease model, we performed transcriptome-wide profiling of fetal muscle (day 90 of pregnancy) from IUGR and normal-weight (NW) littermates. We found that, alongside large-scale transcriptional changes comprising multiple developmental, tissue injury and metabolic gene pathways, KLB was increased in IUGR muscle. Moreover, FGF21 concentrations were increased in plasma in IUGR fetuses. Using cultures of fetal muscle progenitor cells (MPCs), we showed reduced myogenic capacity of IUGR compared to NW muscle in vitro, as evidenced by differences in fusion indices and myogenic transcript levels, as well as mechanistic target of rapamycin (mTOR) activity. Moreover, transfection of MPCs with KLB small interfering RNA promoted myogenesis and mTOR activation, whereas treatment with FGF21 had opposite and dose-dependent effects in porcine and also in human fetal MPCs. In conclusion, our results identify KLB as a novel and potentially critical mediator of impaired muscle development in IUGR, through conserved mechanisms in pigs and humans. Our data shed new light onto the pathogenesis of IUGR, a significant cause of lifelong ill-health in humans and animals. KEY POINTS: Intrauterine growth restriction (IUGR) is associated with large-scale transcriptional changes in developmental, tissue injury and metabolic gene pathways in fetal skeletal muscle. Levels of the fibroblast growth factor 21 (FGF21) co-receptor, beta-Klotho (KLB) are increased in IUGR fetal muscle, and FGF21 concentrations are increased in IUGR fetal plasma. KLB mediates a reduction in muscle development through inhibition of mechanistic target of rapamycin signalling. These effects of KLB on muscle cells are conserved in pig and human, suggesting a vital role of this protein in the regulation of muscle development and function in mammals. CI - (c) 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. FAU - Cortes-Araya, Yennifer AU - Cortes-Araya Y AUID- ORCID: 0000-0002-8456-2152 AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. FAU - Stenhouse, Claire AU - Stenhouse C AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. FAU - Salavati, Mazdak AU - Salavati M AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. FAU - Dan-Jumbo, Susan O AU - Dan-Jumbo SO AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. FAU - Ho, William AU - Ho W AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. FAU - Ashworth, Cheryl J AU - Ashworth CJ AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. FAU - Clark, Emily AU - Clark E AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. FAU - Esteves, Cristina L AU - Esteves CL AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. FAU - Donadeu, F Xavier AU - Donadeu FX AUID- ORCID: 0000-0002-0331-2996 AD - Division of Functional Genetics and Development, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220217 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 SB - IM MH - Animals MH - Female MH - *Fetal Growth Retardation MH - Mammals MH - *Muscle Development MH - Muscle, Skeletal/metabolism MH - Pregnancy MH - Signal Transduction MH - Swine PMC - PMC9303651 OTO - NOTNLM OT - FGF21 OT - IUGR OT - KLB OT - fetal OT - skeletal muscle OT - transcriptome EDAT- 2022/01/27 06:00 MHDA- 2022/04/05 06:00 PMCR- 2022/02/17 CRDT- 2022/01/26 20:08 PHST- 2021/11/20 00:00 [received] PHST- 2022/01/04 00:00 [accepted] PHST- 2022/01/27 06:00 [pubmed] PHST- 2022/04/05 06:00 [medline] PHST- 2022/01/26 20:08 [entrez] PHST- 2022/02/17 00:00 [pmc-release] AID - TJP14956 [pii] AID - 10.1113/JP281647 [doi] PST - ppublish SO - J Physiol. 2022 Apr;600(7):1771-1790. doi: 10.1113/JP281647. Epub 2022 Feb 17.