Maternal Exercise and Paternal Exercise Induce Distinct Metabolite Signatures in Offspring Tissues.

That maternal and paternal exercise improve the metabolic health of adult offspring is well established. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabolites has not yet been investigated. Here, male and female breeders were fed a high-fat diet and housed with or without running wheels before breeding (males) and before and during gestation (females). Offspring were sedentary and chow fed, with parents as follows: sedentary (Sed), maternal exercise (MatEx), paternal exercise (PatEx), or maternal+paternal exercise (Mat+PatEx). Adult offspring from all parental exercise groups had similar improvement in glucose tolerance and hepatic glucose production. Targeted metabolomics was performed in offspring serum, liver, and triceps muscle. Offspring from MatEx, PatEx, and Mat+PatEx each had a unique tissue metabolite signature, but Mat+PatEx offspring had an additive phenotype relative to MatEx or PatEx alone in a subset of liver and muscle metabolites. Tissue metabolites consistently indicated that the metabolites altered with parental exercise contribute to enhanced fatty acid oxidation. These data identify distinct tissue-specific adaptations and mechanisms for parental exercise-induced improvement in offspring metabolic health. Further mining of this data set could aid the development of novel therapeutic targets to combat metabolic diseases.

A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2.

In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK.GALGT2 (also B4GALNT2) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion. Subject 1 (age 8.9 years at dosing) received 2.5 × 1013 vector genome (vg)/kg per leg (5 × 1013 vg/kg total) and subject 2 (age 6.9 years at dosing) received 5 × 1013 vg/kg per leg (1 × 1014 vg/kg total). No serious adverse events were observed. Muscle biopsy evaluated 3 or 4 months post treatment versus baseline showed evidence of GALGT2 gene expression and GALGT2-induced muscle cell glycosylation. Functionally, subject 1 showed a decline in 6-min walk test (6MWT) distance; an increase in time to run 100 m, and a decline in North Star Ambulatory Assessment (NSAA) score until ambulation was lost at 24 months. Subject 2, treated at a younger age and at a higher dose, demonstrated an improvement over 24 months in NSAA score (from 20 to 23 points), an increase in 6MWT distance (from 405 to 478 m), and only a minimal increase in 100 m time (45.6-48.4 s). These data suggest preliminary safety at a dose of 1 × 1014 vg/kg and functional stabilization in one patient.

Exercise-induced 3'-sialyllactose in breast milk is a critical mediator to improve metabolic health and cardiac function in mouse offspring.

Poor maternal environments, such as under- or overnutrition, can increase the risk for the development of obesity, type 2 diabetes and cardiovascular disease in offspring1-9. Recent studies in animal models have shown that maternal exercise before and during pregnancy abolishes the age-related development of impaired glucose metabolism10-15, decreased cardiovascular function16 and increased adiposity11,15; however, the underlying mechanisms for maternal exercise to improve offspring's health have not been identified. In the present study, we identify an exercise-induced increase in the oligosaccharide 3'-sialyllactose (3'-SL) in milk in humans and mice, and show that the beneficial effects of maternal exercise on mouse offspring's metabolic health and cardiac function are mediated by 3'-SL. In global 3'-SL knockout mice (3'-SL-/-), maternal exercise training failed to improve offspring metabolic health or cardiac function in mice. There was no beneficial effect of maternal exercise on wild-type offspring who consumed milk from exercise-trained 3'-SL-/- dams, whereas supplementing 3'-SL during lactation to wild-type mice improved metabolic health and cardiac function in offspring during adulthood. Importantly, supplementation of 3'-SL negated the detrimental effects of a high-fat diet on body composition and metabolism. The present study reveals a critical role for the oligosaccharide 3'-SL in milk to mediate the effects of maternal exercise on offspring's health. 3'-SL supplementation is a potential therapeutic approach to combat the development of obesity, type 2 diabetes and cardiovascular disease.

Maternal Exercise Improves the Metabolic Health of Adult Offspring.

The intrauterine environment can modulate the course of development and confer an enduring effect on offspring health. The effects of maternal diet to impair offspring metabolic health are well established, but the effects of maternal exercise on offspring metabolic health have been less defined. Because physical exercise is a treatment for obesity and type 2 diabetes (T2D), maternal exercise is an appealing intervention to positively influence the intrauterine environment and improve the metabolic health of offspring. Recent research has provided insights into the effects of maternal exercise on the metabolic health of adult offspring, which is the focus of this review.