Julie Rodriguez

Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription

The AMPK/PGC-1α metabolic pathway and nuclear respiratory factor 1 up-regulate human telomere transcription. DNA breaks activate the DNA damage response and, if left unrepaired, trigger cellular senescence. Telomeres are specialized nucleoprotein structures that protect chromosome ends from persistent DNA damage response activation. Whether protection can be enhanced to counteract the age-dependent decline in telomere integrity is a challenging question. Telomeric repeat–containing RNA (TERRA), which is transcribed from telomeres, emerged as important player in telomere integrity. However, how human telomere transcription is regulated is still largely unknown. We identify nuclear respiratory factor 1 and peroxisome proliferator–activated receptor γ coactivator 1α as regulators of human telomere transcription. In agreement with an upstream regulation of these factors by adenosine 5′-monophosphate (AMP)–activated protein kinase (AMPK), pharmacological activation of AMPK in cancer cell lines or in normal nonproliferating myotubes up-regulated TERRA, thereby linking metabolism to telomere fitness. Cycling endurance exercise, which is associated with AMPK activation, increased TERRA levels in skeletal muscle biopsies obtained from 10 healthy young volunteers. The data support the idea that exercise may protect against aging.

Endurance Training Attenuates Catabolic Signals Induced by TNF-α in Muscle of Mice.

PURPOSE To determine whether endurance training attenuates the negative effects induced by an acute injection of tumor necrosis factor-α (TNF-α) in skeletal muscle of mice. METHODS Trained (6 wk of endurance training at 60% of maximal velocity) and untrained mice were injected with TNF-α or vehicle and killed 6 h after. Tibialis anterior muscles were analyzed using Western blot and qRT-PCR for markers of inflammation and protein synthesis/degradation. RESULTS Independently of training, TNF-α increased the mRNA of cytokines and downregulated signals linked to protein synthesis. The phosphorylation of IKKα/β and IκBα induced by TNF-α was blunted in trained mice, suggesting altered NF-κB activation. This was associated with lower induction of several markers of protein degradation (FoxO1, MURF1, MAFbx, myostatin, Gabarapl1, and LC3BII/LC3BI ratio). CONCLUSIONS Endurance training protects skeletal muscle against the activation of protein degradation signaling pathways induced by TNF-α.

Urolithin B, a newly identified regulator of skeletal muscle mass

The control of muscle size is an essential feature of health. Indeed, skeletal muscle atrophy leads to reduced strength, poor quality of life, and metabolic disturbances. Consequently, strategies aiming to attenuate muscle wasting and to promote muscle growth during various (pathological) physiological states like sarcopenia, immobilization, malnutrition, or cachexia are needed to address this extensive health issue. In this study, we tested the effects of urolithin B, an ellagitannin‐derived metabolite, on skeletal muscle growth.

Pomegranate extract prevents skeletal muscle of mice against wasting induced by acute TNF-α injection.

SCOPE We investigated whether punicalagin-rich pomegranate extract (PE) protects skeletal muscle of mice against inflammation induced by an acute injection of TNF-α. RESULTS Mice fed with PE or standard chow during 6 wk were injected with TNF-α (100 ng/g) or vehicle and sacrificed 6 h later. Prior supplementation with PE prevented the loss of tibialis anterior mass induced by TNF-α. In skeletal muscle, the activation of the NF-κB signaling and the induction of cytokines mRNA were reduced in mice having received PE. In those mice, the activity of the Akt/mTORC1 pathway and the protein synthesis were maintained after TNF-α injection whereas markers involved in the ubiquitin proteasome pathway were less activated. As urolithin A was the only punicalagin metabolite detectable in plasma of mice supplemented with PE, we performed in vitro experiments using a murine cell line (C2C12) to provide evidence that urolithin A is likely the active compound protecting skeletal muscle against TNF-α-induced inflammation. CONCLUSION (FOCUS ON NUTRITIONAL RELEVANCE) These results suggest that supplementation with a punicalagin-rich PE may protect skeletal muscle against an acute inflammation.

The gut microbiota metabolite indole alleviates liver inflammation in mice.

The gut microbiota regulates key hepatic functions, notably through the production of bacterial metabolites that are transported via the portal circulation. We evaluated the effects of metabolites produced by the gut microbiota from aromatic amino acids (phenylacetate, benzoate, p‐cresol, and indole) on liver inflammation induced by bacterial endotoxin. Precision‐cut liver slices prepared from control mice, Kupffer cell (KC)‐depleted mice, and obese mice (ob/ob) were treated with or without LPS and bacterial metabolites. We observed beneficial effects of indole that dose‐dependently reduced the LPS‐induced up‐regulation of proinflammatory mediators at both mRNA and protein levels in precision‐cut liver slices prepared from control or ob/ob mice. KC depletion partly prevented the antiinflammatory effects of indole, notably through a reduction of nucleotide‐binding domain and leucine‐rich repeat containing (NLR) family pyrin domain‐containing 3 (NLRP3) pathway activation. In vivo, the oral administration of indole before an LPS injection reduced the expression of key proteins of the NF‐KB pathway and downstream proinflammatory gene up‐regulation. Indole also prevented LPS‐induced alterations of cholesterol metabolism through a transcriptional regulation associated with increased 4β‐hydroxycholesterol hepatic levels. In summary, indole appears as a bacterial metabolite produced from tryptophan that is able to counteract the detrimental effects of LPS in the liver. Indole could be a new target to develop innovative strategies to decrease hepatic inflammation.—Beaumont, M., Neyrinck, A. M., Olivares, M., Rodriguez, J., de Rocca Serra, A., Roumain, M., Bindels, L. B., Cani, P. D., Evenepoel, P., Muccioli, G. G., Demoulin, J.‐B., Delzenne, N. M. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J. 32, 6681–6693 (2018). www.fasebj.org

Inulin Improves Postprandial Hypertriglyceridemia by Modulating Gene Expression in the Small Intestine

Postprandial hyperlipidemia is an important risk factor for cardiovascular diseases in the context of obesity. Inulin is a non-digestible carbohydrate, known for its beneficial properties in metabolic disorders. We investigated the impact of inulin on postprandial hypertriglyceridemia and on lipid metabolism in a mouse model of diet-induced obesity. Mice received a control or a western diet for 4 weeks and were further supplemented or not with inulin for 2 weeks (0.2 g/day per mouse). We performed a lipid tolerance test, measured mRNA expression of genes involved in postprandial lipid metabolism, assessed post-heparin plasma and muscle lipoprotein lipase activity and measured lipid accumulation in the enterocytes and fecal lipid excretion. Inulin supplementation in western diet-fed mice decreases postprandial serum triglycerides concentration, decreases the mRNA expression levels of Cd36 (fatty acid receptor involved in lipid uptake and sensing) and apolipoprotein C3 (Apoc3, inhibitor of lipoprotein lipase) in the jejunum and increases fecal lipid excretion. In conclusion, inulin improves postprandial hypertriglyceridemia by targeting intestinal lipid metabolism. This work confirms the interest of using inulin supplementation in the management of dyslipidemia linked to obesity and cardiometabolic risk.