Maternal diet during pregnancy is associated with offspring metabolic risk trajectory in humans and animal models, but the prenatal origins of these effects are less clear. We examined the effects of a high-fat diet (HFD) during pregnancy on fetal skeletal muscle metabolism and metabolic risk parameters using an ovine model. White-faced ewes were fed a standardized diet containing 5% fat wt/wt (CON), or the same diet supplemented with 6% rumen-protected fats (11% total fat wt/wt; HFD) beginning 2 wk before mating until midgestation (GD75). Maternal HFD increased maternal weight gain, fetal body weight, and low-density lipoprotein levels in the uterine and umbilical circulation but had no significant effects on circulating glucose, triglycerides, or placental fatty acid transporters. Fatty acid (palmitoylcarnitine) oxidation capacity of permeabilized hindlimb muscle fibers was >50% higher in fetuses from HFD pregnancies, whereas pyruvate and maximal (mixed substrate) oxidation capacities were similar to CON. This corresponded to greater triacylglycerol content and protein expression of fatty acid transport and oxidation enzymes in fetal muscle but no significant effect on respiratory chain complexes or pyruvate dehydrogenase expression. However, serine-308 phosphorylation of insulin receptor substrate-1 was greater in fetal muscle from HFD pregnancies along with c-jun-NH2 terminal kinase activation, consistent with prenatal inhibition of skeletal muscle insulin signaling. These results indicate that maternal high-fat feeding shifts fetal skeletal muscle metabolism toward a greater capacity for fatty acid over glucose utilization and favors prenatal development of insulin resistance, which may predispose offspring to metabolic syndrome later in life.NEW & NOTEWORTHY Maternal diet during pregnancy is associated with offspring metabolic risk trajectory in humans and animal models, but the prenatal origins of these effects are less clear. This study examined the effects of a high-fat diet during pregnancy on metabolic risk parameters using a new sheep model. Results align with findings previously reported in nonhuman primates, demonstrating changes in fetal skeletal muscle metabolism that may predispose offspring to metabolic syndrome later in life.

Pulmonary hypertension is a noninfectious disease of cattle at altitudes > 1524 m (5,000 ft). Mean pulmonary arterial pressures (PAP) are used as an indicator for pulmonary hypertension in cattle. High PAP cattle (>= 50 mmHg) entering the feedlot at moderate elevations have lower feed efficiency as compared to low PAP cattle (< 50 mmHg). The impact of pulmonary arterial pressure on mitochondrial function, oxidative phosphorylation (OXPHOS) protein abundance, and meat color was examined using longissimus lumborum (LL) from high (98 +/- 13 mmHg; n = 5) and low (41 +/- 3 mmHg; n = 6) PAP fattened Angus steers (live weight of 588 +/- 38 kg) during early postmortem period (2 and 48 h) and retail display (days 1 to 9), respectively. High PAP muscle had greater (P = 0.013) OXPHOS-linked respiration and proton leak-associated respiration than low PAP muscles at 2 h postmortem but rapidly declined to be similar (P = 0.145) to low PAP muscle by 48 h postmortem. OXPHOS protein expression was higher (P = 0.045) in low PAP than high PAP muscle. During retail display, redness, chroma, hue, ratio of reflectance at 630 and 580 nm, and metmyoglobin reducing activity decreased faster (P < 0.05) in high PAP steaks than low PAP. Lipid oxidation significantly increased (P < 0.05) in high PAP steaks but not (P > 0.05) in low PAP. The results indicated that high PAP caused a lower OXPHOS efficiency and greater fuel oxidation rates under conditions of low ATP demand in premortem beef LL muscle; this could explain the lower feed efficiency in high PAP feedlot cattle compared to low PAP counterparts. Mitochondrial integral function (membrane integrity or/and protein function) declined faster in high PAP than low PAP muscle at early postmortem. LL steaks from high PAP animals had lower color stability than those from the low PAP animals during simulated retail display, which could be partially attributed to the loss of muscle mitochondrial function at early postmortem by ROS damage in high PAP muscle. High pulmonary arterial pressure (PAP) caused a lower oxidative phosphorylation efficiency and greater fuel oxidation rates under conditions of low ATP demand in beef longissimus lumborum(LL) muscle. Moreover, LL steaks from high PAP animals had lower color stability than those from the low PAP animals during simulated retail display, which could be partially attributed to the faster decline of mitochondrial integral function in high PAP than low PAP muscle at early postmortem. Lay Summary The impact of pulmonary arterial pressure (PAP) on mitochondrial function, oxidative phosphorylation protein abundance, and meat color was examined using longissimus lumborum (LL) from high (98 +/- 13 mmHg) and low (41 +/- 3 mmHg) PAP fattened Angus steers (live weight of 588 +/- 38 kg) during early postmortem period (2 and 48 h) and retail display (days 1 to 9), respectively. The results indicated that high PAP caused a lower oxidative phosphorylation efficiency and greater fuel oxidation rates under conditions of positive energy balance in beef LL muscle. This could explain the lower feed efficiency in high PAP feedlot cattle compared to low PAP counterparts. Mitochondrial integral function declined faster in high PAP than low PAP muscle at early postmortem. LL steaks from high PAP animals had lower color stability than those from the low PAP animals during simulated retail display, which could be partially attributed to the loss of muscle mitochondrial function at early postmortem in high PAP muscle

Dietary supplementation of omega-3 fatty acids such as docosahexaenoic acid (DHA) during pregnancy is often recommended to support optimal fetal brain development and cognitive function of the offspring. DHA supplementation also influences cardiometabolic risk parameters in adults, but its effect on fetal metabolism and subsequent risk is poorly understood. The aim of this study was to determine the effects of maternal DHA supplementation (MDS) on placental and fetal nutrient handling during pregnancy. White-faced ewes were fed either a control diet (Show-rite NewCo Lamb Feed) or a DHA-supplemented diet (control diet + 3% w/w algae-derived DHA) from 2–3 weeks before pregnancy until mid-gestation (75 days), after which a C-section was performed to collect the placenta and fetal tissues for metabolic analyses. MDS significantly increased serum DHA levels and decreased serum triglycerides in the uterine (maternal) circulation, but not umbilical (fetal) circulation. Nevertheless, MDS resulted in significant DHA enrichment of the placenta and all fetal tissues examined, and differentially affected the protein expression of the four major fatty acid transport proteins FATP1, FATP4, CD36 and FABP in placenta, muscle, liver and heart, but had no effect on kidney or brain. Consistent with these findings, MDS tended to increase the capacity for fat over pyruvate oxidation in fetal muscle and heart, but favored a greater capacity for glucose uptake and oxidation in fetal liver. This study is the first to validate use of an ovine model for investigating the impact of maternal DHA supplementation on fetal metabolism and development. Results demonstrate a complex tissue-specific effect of MDS on fetal tissue carbohydrate and fatty acid metabolism that favors a greater capacity for serum glucose disposal and fatty acid oxidation. Whether these changes ultimately impact nutrient metabolism and cardiometabolic risk in the offspring later in life merits further investigation. Colorado Agricultural Experiment Station.

Barth syndrome (BTHS) is an X-linked disorder that results from mutations in the TAFAZZIN gene, which encodes a phospholipid transacylase responsible for generating the mature form of cardiolipin in inner mitochondrial membranes. BTHS patients develop early onset cardiomyopathy and a derangement of intermediary metabolism consistent with mitochondrial disease, but the precise alterations in cardiac metabolism that distinguish BTHS from idiopathic forms of cardiomyopathy are unknown. We performed the first metabolic analysis of myocardial tissue from BTHS cardiomyopathy patients compared to age- and sex-matched patients with idiopathic dilated cardiomyopathy (DCM) and nonfailing controls. Results corroborate previous evidence for deficiencies in cardiolipin content and its linoleoyl enrichment as defining features of BTHS cardiomyopathy, and reveal a dramatic accumulation of hydrolyzed (monolyso-) cardiolipin molecular species. Respiratory chain protein deficiencies were observed in both BTHS and DCM, but a selective depletion of complex I was seen only in BTHS after controlling for an apparent loss of mitochondrial density in cardiomyopathic hearts. Distinct shifts in the expression of long-chain fatty acid oxidation enzymes and the tissue acyl-CoA profile of BTHS hearts suggest a specific block in mitochondrial fatty acid oxidation upstream of the conventional matrix beta-oxidation cycle, which may be compensated for by a greater reliance upon peroxisomal fatty acid oxidation and the catabolism of ketones, amino acids, and pyruvate to meet cardiac energy demands. These results provide a comprehensive foundation for exploring novel therapeutic strategies that target the adaptive and maladaptive metabolic features of BTHS cardiomyopathy.

Excessive maternal dietary fat consumption during pregnancy may be linked to adverse effects on offspring health, including greater risk of developing metabolic syndrome later in life. Metabolic syndrome is generally considered to be a preventable condition, but the extent to which it is “programmed” during fetal development remains unclear. The aim of this study was to determine the effect of a maternal high-fat diet (MHFD) during pregnancy on fetal muscle oxidative metabolism and related protein and mRNA expressions in an ovine model. White-faced ewes were fed either a control diet (Show-rite NewCo Lamb Feed-17% protein, 5% Fat) or a high-fat diet (Show-rite NewCo Lamb Feed + 6% Rumen-protected Fat) from 2–3 weeks before pregnancy until mid-gestation (75 days), when a C-section was performed to collect the placenta and fetal tissues for analysis. MHFD tended to increase fetal body and organ weights, but only significantly increased fetal body length and liver mass (P < 0.05). MHFD increased mRNA expression of placental (cotyledon) fatty acid transport protein-1 (FATP-1) and peroxisome proliferator activated receptor gamma, suggesting an upregulation of placental fatty acid metabolism and transport. Fetal muscle fatty acid oxidation capacity was greater in animals from MHFD pregnancies, with no effect on pyruvate oxidation. This was associated with greater fetal muscle mRNA and protein expression of FATP4, while mRNA expression glucose transporters (GLUT1 and GLUT3) decreased. Muscle expression of insulin signaling enzymes reflected a mild decreases in insulin sensitivity, but these did not reach statistical significance. These studies indicate that MHFD induces an increase in placental and fetal muscle fatty acid transport and oxidation capacity, and favors lower blood glucose uptake compared to controls. Whether these shifts in fetal metabolism predispose offspring from MHFD pregnancies to elevated blood sugar and Type 2 diabetes later in life merits further investigation. Colorado Agricultural Experiment Station.

The chemotherapy drug doxorubicin (DOX) has been shown to cause skeletal muscle dysfunction when measured ex vivo, but little is known about the effects of DOX on in vivo skeletal muscle function. The aim of this study was to examine the effects of two different bolus DOX treatments on skeletal muscle function measured in vivo using a rat grip strength meter. Baseline grip strength was assessed prior to rats receiving intraperitoneal injections of 10 mg/kg DOX (DOX1), 15 mg/kg DOX (DOX2), or saline as a control (CON). Grip strength was then assessed daily for seven days. At baseline, no between group differences in grip strength were observed, but a between group difference was observed at day four with DOX2 having a lower grip strength than CON and DOX1. This reduced grip strength in DOX2 continued through day seven. DOX1 had reduced grip strength when compared to CON only at day six. These results suggest that DOX administration affects in vivo skeletal muscle function in a dose‐dependent manner. As such, this model provides a novel approach for analyzing DOX myotoxicity and interventions aimed at minimizing this side effect.