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Undernutrition-induced growth restriction in the early stages of life increases the risk of chronic disease in adulthood. Although metabolic impairments have been observed, few studies have characterized the gut microbiome and gut-liver metabolome profiles of growth-restricted animals during early-to-mid-life development. To induce growth restriction, mouse offspring were either born to gestational undernutrition (GUN) or suckled from postnatal undernutrition (PUN) dams fed a protein-restricted diet (8% protein) or control diet (CON; 20% protein) until weaning at postnatal age of 21 days (PN21). At PN21, all mice were fed the CON diet until adulthood (PN80). Livers were collected at PN21 and PN80, and fecal samples were collected weekly starting at PN21 (

Introduction A total of 161 million children a year are growth restricted, leading to a 47% increased risk of chronic disease in adulthood. Physical activity (PA) reduces the risk of mortality from chronic disease. The purpose of the present investigation was to determine the effect of a PA intervention (wheel running) on cardiac and skeletal muscle capacities in gestational (GUN) and postnatal (PUN) growth-restricted mice as compared with nonrestricted controls (CON). Methods A low-protein cross-fostering FVB mouse model was used to induce growth restriction during gestation and the first 21 d of postnatal life. Mouse pups were recovered on a healthy diet until mature and provided wheel access for 3 wk. At completion of the PA intervention, mice underwent maximal exercise testing on a treadmill, echocardiography, and skeletal muscle histology. Results After the PA intervention, CON mice had a 45% improvement in maximal exercise capacity (P = 0.0390) because of cardiac and skeletal muscle adaptations, but GUN and PUN mice did not. Alarmingly, PUN female mice exposed to wheels had 11.45% lower left ventricular volume (P = 0.0540) and 18% lower left ventricle area (P = 0.0585), with blood flow velocities indicative of cardiac fibrosis (GUN had elevated isovolumetric contraction time P = 0.0374; GUN females and PUN males had longer isovolumetric relaxation time P = 0.0703). PUN male mice had mixed skeletal muscle responses with an oxidative shift in the diaphragm (P = 0.0162) but a glycolytic shift in the extensor digitorum longus (P = 0.0647). PUN female mice had a glycolytic shift in the soleus after wheel running. Conclusions Unexpectedly, growth-restricted mice were nonresponders to a PA intervention and displayed negative cardiac outcomes.

Postnatal growth restriction (PGR) increases the risk for cardiovascular disease (CVD) in adulthood, yet there is minimal mechanistic rationale for the observed pathology. The purpose of this study was to identify proteomic differences in hearts of growth-restricted and unrestricted mice, and propose mechanisms related to impairment in adulthood. Friend leukemia virus B (FVB) mouse dams were fed a control (CON: 20% protein), or low-protein (LP: 8% protein) isocaloric diet 2 weeks before mating. LP dams produce 20% less milk, inducing growth restriction. At birth (postnatal, PN1), pups born to dams fed the CON diet were switched to LP dams (PGR group) or a different CON dam. At PN21, a sub-cohort of CON (n = 3 males, n = 3 females) and PGR (n = 3 males, n = 3 females) were euthanized and their proteome analyzed by two-dimensional differential in-gel electrophoresis (2D DIGE) and mass spectroscopy. Western blotting and silver nitrate staining confirmed 2D DIGE results. Littermates (CON: n = 4 males and n = 4 females, PGR: n = 4 males and n = 4 females) were weaned to the CON diet. At PN77, echocardiography measured cardiac function. At PN80, hearts were removed for western blotting to determine if differences persisted into adulthood. 2D DIGE and western blot confirmation indicated PGR had reductions in p57kip2, Titin (Ttn), and Collagen (Col). At PN77, PGR had impaired cardiac function as measured by echocardiography. At PN80, western blots of p57kip2 showed protein abundance recovered from PN21. PN80 silver staining of large molecular weight proteins (Ttn and Col) was reduced in PGR. PGR reduces cell cycle activity at PN21, which is recovered in adulthood. However, collagen fiber networks are altered into adulthood.

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1–9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches11–13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis. Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.

Quadriceps muscle weakness is a commonly reported issue post anterior cruciate ligament reconstruction (ACLR), with minimal information related to skeletal muscle morphology following surgery. The purpose is to examine the morphological and functional differences in the vastus lateralis muscle from patient's ACLR and contralateral leg. Three physically active ACLR participants were recruited and secured to a dynamometer to perform maximal voluntary isometric knee extension contractions (MVIC) of the ACLR and contralateral limb. Muscle biopsies of the ACLR and contralateral vastus lateralis were performed, then sectioned, and stained for myosin isoforms to determine fiber type. Confocal images were acquired, and ImageJ software was used to determine the fiber type and cross-sectional area (CSA). There was a significant reduction in CSA of the type IIa and type IIx muscle fiber cells between healthy (IIa: 7,718 ± 1,295 µm2; IIx; 5,800 ± 601 µm2) and ACLR legs (IIa: 4,139 ± 709 µm2; IIx: 3,708 ± 618 µm2) (p

INTRODUCTION The purpose of this study was to determine the effect of growth restriction on the biological regulation of physical activity. METHODS Using a cross-fostering, protein-restricted nutritive model, mice were growth-restricted during either gestation (GUN; N = 3 litters) or postnatal life (PUN; N = 3 litters). At 21 d of age, all mice pups were weaned and fed a nonrestrictive healthy diet for the remainder of the study. At 45 d of age, mice were individually housed in cages with free moving running wheels to assess physical activity engagement. At day 70, mice were euthanized, and the nucleus accumbens was analyzed for dopamine receptor 1 expression. Skeletal muscle fiber type and cross-sectional area of the soleus, extensor digitorom longus, and diaphragm were analyzed by immunohistochemistry. The soleus from the other hindleg was evaluated for calsequestrin 1 and annexin A6 expression. RESULTS The PUN female mice (15,365 ± 8844 revolutions per day) had a reduction (P = 0.0221) in wheel revolutions per day as compared with the GUN (38,667 ± 8648 revolutions per day) and CON females (36,421.0 ± 6700 revolutions per day). The PUN female mice also expressed significantly higher dopamine receptor 1 compared (P = 0.0247) to the other groups. The PUN female soleus had a higher expression of calsequestrin 1, along with more type IIb fibers (P = 0.0398). CONCLUSIONS Growth restriction during lactation reduced physical activity in female mice by reducing the central drive to be active and displayed a more fatigable skeletal muscle phenotype.