Enhanced transforming growth factor β (TGF‐β) signaling and fibrogenesis in fetal skeletal muscle of obese sheep at late gestation

Abstract

INTRODUCTIONMaternal obesity is increasing at an alarming rate. The objective of this studywas to evaluate the effect of maternal obesity on fibrogenesis in fetal skeletal muscle in late gestation when ovine fetal muscle matures.METHODSNon‐pregnantewes were assigned to a control (Con, fed 100% of NRCnutrient recommendations, n = 6) or obesogenic (OB, fed150% of NRC recommendations, n = 6) diet from 60 days before to 135 days after conception (gestation =148 days) when the fetal semitendenosus (St) muscle wassampled for trichrome staining, immunoblotting and real‐time quantitative PCR analyses.RESULTSThe total area of collagen in the cross‐sections of St muscle increased by 105.1 ± 5.9% (P = 0.05) in fetuses of OB compared with Con mothers. The expression of precursor TGF‐β in OB fetal muscle was 177.3 ± 47.6% higher (P < 0.05) than Con fetal muscle, indicating activation of TGF‐β signaling. p38 promotes TGF‐β signaling; the concentration of phospho‐p38 was 74.7 ± 23.6% higher (P < 0.05) in OB fetal muscle, as well as the ratio of phospho‐p38/total p38 (83.2 ± 20.4%, P < 0.05). The mRNA expression of Smad7 and fibronectin is regulated by TGF‐β signaling. An increase of 327.9 ± 168.0% (P < 0.05) and 188.9 ± 82.1% (P < 0.05) respectively was observed for the mRNA expression of Smad7 and fibronectin in OB fetal muscle compared with Con.CONCLUSIONSThese data demonstrate that maternal obesity enhanced fibrogenesis in fetal muscle in late gestation associated with up‐regulation of the TGF‐β/p38 signaling pathway. These changes are expected to negatively affect the properties of offspring skeletal muscle. (Supported by NIH 1R03HD057506 and Wyoming INBRE P20RR016474)