442 Awardee Talk: Adaptive Programming of Poor Skeletal Muscle Growth and Metabolism Associated with Heat Stress-Induced Intrauterine Growth Restriction
Authors: Gibbs Rachel L , Swanson Rebecca , Beard Joselyn K , Clement Shawna M , Hicks Zena M , Grijalva Pablo , White Melanie R , Peterson Jessica L L , Schmidt Ty B B , Yates Dustin T 
Published: November 2023

Abstract
Intrauterine growth restriction (IUGR) is associated with reduced β2 adrenergic sensitivity, which contributes to poor postnatal muscle growth and metabolic inefficiency. Thus, our objective was to determine if stimulating β2 adrenergic activity would rescue deficits in muscle growth, body composition, and indicators of metabolic homeostasis in IUGR offspring. Maternal heat stress (40°C, 35% humidity, THI = 85) from d 40 to 95 of gestation was used to produce IUGR lambs. From birth, IUGR lambs received daily IM injections of saline (IUGR; n = 12) or 0.8 μg/kg clenbuterol HCl (IUGR+CLEN; n = 11). Placebo-injected controls (n = 13) were born to pair-fed thermoneutral ewes. Body composition was estimated by ultrasound and bioelectrical impedance analyses (BIA) at d 58. Lambs were catheterized at d 55 and necropsied at d 60. Square-wave hyperglycemic clamps and indirect calorimetry were performed at d 57. Hyperinsulinemic-euglycemic clamps were performed at d 58. Bodyweights were lighter (P ≤ 0.05) for IUGR and IUGR+CLEN lambs than for controls at birth, d 30, and d 60. Average daily gain was less (P ≤ 0.05) for IUGR compared with controls and was intermediate for IUGR+CLEN lambs. BIA-estimated fat-free mass, ultrasound-estimated loin eye area (LEA), actual LEA, and flexor digitorum superficialis (FDS) muscle weight were less (P ≤ 0.05) for IUGR but not IUGR+CLEN lambs than for controls. Semitendinosus from IUGR lambs had less (P ≤ 0.05) β2 adrenoreceptor content, fewer (P ≤ 0.05) proliferating myoblasts, tended to have fewer (P = 0.08) differentiated myoblasts, and had smaller (P ≤ 0.05) muscle fibers than controls. Proliferating myoblasts and fiber size but not β2 adrenoreceptor content or differentiated myoblasts were rescued (P ≤ 0.05) in IUGR+CLEN lambs compared with IUGR lambs. Basal plasma insulin did not differ, but glucose-stimulated insulin secretion was 44% less (P ≤ 0.05) for IUGR lambs than for controls and was intermediate for IUGR+CLEN lambs. Basal and insulin-stimulated hindlimb glucose uptake and basal glucose oxidation did not differ among groups. Insulin-stimulated glucose oxidation was 54% less (P ≤ 0.05) for IUGR lambs but not IUGR+CLEN lambs compared with controls. Ex vivo glucose uptake was 25% less (P ≤ 0.05) for FDS from IUGR and IUGR+CLEN lambs than from controls. Ex vivo glucose oxidation was less (P ≤ 0.05) for FDS and soleus from IUGR lambs compared with controls and was intermediate (P ≤ 0.05) for FDS but not soleus from IUGR+CLEN lambs. Whole-body O2 consumption was 22% less (P ≤ 0.05) for IUGR and IUGR+CLEN lambs than for controls. Whole-body CO2 production was 17% less (P ≤ 0.05) for IUGR but not IUGR+CLEN lambs than for controls. These findings show that IUGR muscle remained responsive to β2 adrenergic stimulation despite reduced β2 adrenoreceptor content, and thus β2 adrenergic pathways may be a strategic target for improving muscle growth, body composition, and metabolic efficiency in IUGR-born offspring.