Impaired muscle stem cell function in cows with high concentrations of androstenedione in their follicular fluid

It is unclear whether androstenedione (A4) increases muscle mass and strength similar to testosterone or whether it produces primarily catabolic effects on muscle-like estrogen (Rasmussen et al., 2000). Summers et al. (2014) observed two populations of cows that exhibit either high (\u3e40 ng/mL; High A4) or low (\u3c20 ng/mL; Low A4) concentrations of A4 within the fluid of the dominant follicle just prior to ovulation. High A4 cows had decreased reproductive rates and shorter times before falling out of the herd, but those that did produce calves weaned them ~10-kg heavier than their low A4 counterparts (Summers et al., 2014). It appears that the difference in weights is due to faster growing and more efficient skeletal muscle. High A4 cows share many characteristics with women suffering from polycystic ovary syndrome (PCOS), whose high levels of circulating androgens are associated with changes in body composition (Kirchengast and Huber, 2001)

Primary myoblasts from intrauterine growth-restricted fetal sheep exhibit intrinsic dysfunction of proliferation and differentiation that coincides with enrichment of inflammatory cytokine signaling pathways

Intrauterine growth restriction (IUGR) is linked to lifelong reductions in muscle mass due to intrinsic functional deficits in myoblasts, but the mechanisms underlying these deficits are not known. Our objective was to determine if the deficits were associated with changes in inflammatory and adrenergic regulation of IUGR myoblasts, as was previously observed in IUGR muscle. Primary myoblasts were isolated from IUGR fetal sheep produced by hyperthermia-induced placental insufficiency (PI-IUGR; n = 9) and their controls (n = 9) and from IUGR fetal sheep produced by maternofetal inflammation (MI-IUGR; n = 6) and their controls (n = 7). Proliferation rates were less (P \u3c 0.05) for PI-IUGR myoblasts than their controls and were not affected by incubation with IL-6, TNF-α, norepinephrine, or insulin. IκB kinase inhibition reduced (P \u3c 0.05) proliferation of control myoblasts modestly in basal media but substantially in TNF-α-added media and reduced (P \u3c 0.05) PI-IUGR myoblast proliferation substantially in basal and TNF-α-added media. Proliferation was greater (P \u3c 0.05) for MI-IUGR myoblasts than their controls and was not affected by incubation with TNF-α. Insulin increased (P \u3c 0.05) proliferation in both MI-IUGR and control myoblasts. After 72-h differentiation, fewer (P \u3c 0.05) PI-IUGR myoblasts were myogenin+ than controls in basal and IL-6 added media but not TNF-α-added media. Fewer (P \u3c 0.05) PI-IUGR myoblasts were desmin+ than controls in basal media only. Incubation with norepinephrine did not affect myogenin+ or desmin+ percentages, but insulin increased (P \u3c 0.05) both markers in control and PI-IUGR myoblasts. After 96-h differentiation, fewer (P \u3c 0.05) MI-IUGR myoblasts were myogenin+ and desmin+ than controls regardless of media, although TNF-α reduced (P \u3c 0.05) desmin+ myoblasts for both groups. Differentiated PI-IUGR myoblasts had greater (P \u3c 0.05) TNFR1, ULK2, and TNF-α-stimulated TLR4 gene expression, and PI-IUGR semitendinosus muscle had greater (P \u3c 0.05) TNFR1 and IL6 gene expression, greater (P \u3c 0.05) c-Fos protein, and less (P \u3c 0.05) IκBα protein. Differentiated MI-IUGR myoblasts had greater (P \u3c 0.05) TNFR1 and IL6R gene expression, tended to have greater (P = 0.07) ULK2 gene expression, and had greater (P \u3c 0.05) β-catenin protein and TNF-α-stimulated phosphorylation of NFκB. We conclude that these enriched components of TNF-α/TNFR1/NFκB and other inflammatory pathways in IUGR myoblasts contribute to their dysfunction and help explain impaired muscle growth in the IUGR fetus. Lay Summary-- Myoblasts are stems cells whose functional capacity can limit muscle growth. However, stressful intrauterine conditions cause these cells to be intrinsically dysfunctional. This restricts muscle growth capacity, leading to intrauterine growth restriction (IUGR) of the fetus, low birth weight, and less muscle mass after birth. Consequently, meat yield is reduced in IUGR-born food animals and glucose homeostasis is impaired in IUGR-born humans, which contributes to metabolic dysfunction. Intrinsic dysfunction of IUGR myoblasts has been previously observed, but the fetal programming changes (i.e., permanent changes in the development of cellular mechanisms that explains different functional outcomes) have not been identified. This study shows that one mechanism is the enhancement of signaling pathways for TNF-α and other inflammatory cytokines. These cytokines have roles in stress responses and regulation of muscle growth. Programmed enhancement of these pathways means that IUGR myoblasts are more responsive to even normal amounts of circulating cytokines. Unfortunately, the primary response of myoblasts to cytokines is slower differentiation (i.e., cellular transformation necessary for muscle growth). Programmed enhancement of this response directly impedes myoblast-dependent muscle growth, and the deficit is lifelong. However, identifying this mechanism is a fundamental step for developing strategies to improve muscle growth in low birth weight offspring

Impaired muscle stem cell function in cows with high concentrations of androstenedione in their follicular fluid

It is unclear whether androstenedione (A4) increases muscle mass and strength similar to testosterone or whether it produces primarily catabolic effects on muscle-like estrogen (Rasmussen et al., 2000). Summers et al. (2014) observed two populations of cows that exhibit either high (\u3e40 ng/mL; High A4) or low (\u3c20 ng/mL; Low A4) concentrations of A4 within the fluid of the dominant follicle just prior to ovulation. High A4 cows had decreased reproductive rates and shorter times before falling out of the herd, but those that did produce calves weaned them ~10-kg heavier than their low A4 counterparts (Summers et al., 2014). It appears that the difference in weights is due to faster growing and more efficient skeletal muscle. High A4 cows share many characteristics with women suffering from polycystic ovary syndrome (PCOS), whose high levels of circulating androgens are associated with changes in body composition (Kirchengast and Huber, 2001)