Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay.

OBJECTIVE: To investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health. DESIGN: A double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients. RESULTS: Over 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut. CONCLUSION: The present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota. TRIAL REGISTRATION NUMBER: NCT02099032 and NCT02146339; Results.

Fast digestive, leucine-rich, soluble milk proteins improve muscle protein anabolism, and mitochondrial function in undernourished old rats.

SCOPE: One strategy to manage malnutrition in older patients is to increase protein and energy intake. Here, we evaluate the influence of protein quality during refeeding on improvement in muscle protein and energy metabolism. METHODS AND RESULTS: Twenty-month-old male rats (n = 40) were fed 50% of their spontaneous intake for 12 weeks to induce malnutrition, then refed ad libitum with a standard diet enriched with casein or soluble milk proteins (22%) for 4 weeks. A 13C-valine was infused to measure muscle protein synthesis and expression of MuRF1, and MAFbx was measured to evaluate muscle proteolysis. mTOR pathway activation and mitochondrial function were assessed in muscle. Malnutrition was associated with a decrease in body weight, fat mass, and lean mass, particularly muscle mass. Malnutrition decreased muscle mTOR pathway activation and protein FSR associated with increased MuRF1 mRNA levels, and decreased mitochondrial function. The refeeding period partially restored fat mass and lean mass. Unlike the casein diet, the soluble milk protein diet improved muscle protein metabolism and mitochondrial function in old malnourished rats. CONCLUSIONS: These results suggest that providing better-quality proteins during refeeding may improve efficacy of renutrition in malnourished older patients.

Muscle metabolic alterations induced by genetic ablation of 4E-BP1 and 4E-BP2 in response to diet-induced obesity.

SCOPE: In recent years, several studies reported the role of eIF4E-binding proteins (4E-BPs) on the development of diet-induced obesity and insulin resistance. Our aim was to investigate the effect of 4E-BP protein deletion on lipid accumulation and metabolism in skeletal muscle in response to a high-fat diet induced obesity in 4E-BP1/2 DKO mice. METHODS AND RESULTS: Diet-induced obesity engendered increased ectopic accumulation of lipotoxic species in skeletal muscle of 4E-BP1 and 4E-BP2 double knockout mice (4E-BP1/2 DKO), namely diacylglycerols and ceramides. Increased lipid accumulation was associated with alterations in the expression of genes involved in fatty acid transport (FATP, CD36), diacylglycerol/triacylglycerol biosynthesis (GPAT1, AGPAT1, DGAT1), and ß-oxidation (CPT1b, MCAD). Diet-induced obesity resulted in increased lean mass and muscle in 4E-BP1/2 DKO mice despite the development of a more severe systemic insulin resistance. Since increased expression of genes of several proteolytic systems (MuRF1, atrogin/MAFbx, and cathepsin-l) in 4EBP1/2 DKO skeletal muscle was reported, the increase of skeletal muscle mass in 4E-BP1/2 DKO mice suggests that ablation of 4E-BPs compensate with activation of muscle anabolism. CONCLUSIONS: These findings indicate that 4E-BP proteins may prevent excess lipid accumulation in skeletal muscle and suggest that 4E-BPs are key regulators of muscle homeostasis regardless of insulin sensitivity.

Vitamin D supplementation restores the blunted muscle protein synthesis response in deficient old rats through an impact on ectopic fat deposition.

We investigated the impact of vitamin D deficiency and repletion on muscle anabolism in old rats. Animals were fed a control (1 IU vitamin D3/g, ctrl, n=20) or a vitamin D-depleted diet (VDD; 0 IU, n=30) for 6 months. A subset was thereafter sacrificed in the control (ctrl6) and depleted groups (VDD6). Remaining control animals were kept for 3 additional months on the same diet (ctrl9), while a part of VDD rats continued on a depleted diet (VDD9) and another part was supplemented with vitamin D (5 IU, VDS9). The ctr16 and VDD6 rats and the ctr19, VDD9 and VDS9 rats were 21 and 24 months old, respectively. Vitamin D status, body weight and composition, muscle strength, weight and lipid content were evaluated. Muscle protein synthesis rate (fractional synthesis rate; FSR) and the activation of controlling pathways were measured. VDD reduced plasma 25(OH)-vitamin D, reaching deficiency (<25 nM), while 25(OH)-vitamin D increased to 118 nM in the VDS group (P<.0001). VDD animals gained weight (P<.05) with no corresponding changes in lean mass or muscle strength. Weight gain was associated with an increase in fat mass (+63%, P<.05), intramyocellular lipids (+75%, P<.05) and a trend toward a decreased plantaris weight (-19%, P=.12). Muscle FSR decreased by 40% in the VDD group (P<.001), but was restored by vitamin D supplementation (+70%, P<.0001). Such changes were linked to an over-phosphorylation of eIF2α. In conclusion, vitamin D deficiency in old rats increases adiposity and leads to reduced muscle protein synthesis through activation of eIF2α. These disorders are restored by vitamin D supplementation.

Vitamin D and muscle trophicity.

PURPOSE OF REVIEW: We review recent findings on the involvement of vitamin D in skeletal muscle trophicity. RECENT FINDINGS: Vitamin D deficiencies are associated with reduced muscle mass and strength, and its supplementation seems effective to improve these parameters in vitamin D-deficient study participants. Latest investigations have also evidenced that vitamin D is essential in muscle development and repair. In particular, it modulates skeletal muscle cell proliferation and differentiation. However, discrepancies still exist about an enhancement or a decrease of muscle proliferation and differentiation by the vitamin D. Recently, it has been demonstrated that vitamin D influences skeletal muscle cell metabolism as it seems to regulate protein synthesis and mitochondrial function. Finally, apart from its genomic and nongenomic effects, recent investigations have demonstrated a genetic contribution of vitamin D to muscle functioning. SUMMARY: Recent studies support the importance of vitamin D in muscle health, and the impact of its deficiency in regard to muscle mass and function. These 'trophic' properties are of particular importance for some specific populations such as elderly persons and athletes, and in situations of loss of muscle mass or function, particularly in the context of chronic diseases.

Skeletal muscle regeneration and impact of aging and nutrition.

After skeletal muscle injury a regeneration process takes place to repair muscle. Skeletal muscle recovery is a highly coordinated process involving cross-talk between immune and muscle cells. It is well known that the physiological activities of both immune cells and muscle stem cells decline with advancing age, thereby blunting the capacity of skeletal muscle to regenerate. The age-related reduction in muscle repair efficiency contributes to the development of sarcopenia, one of the most important factors of disability in elderly people. Preserving muscle regeneration capacity may slow the development of this syndrome. In this context, nutrition has drawn much attention: studies have demonstrated that nutrients such as amino acids, n-3 polyunsaturated fatty acids, polyphenols and vitamin D can improve skeletal muscle regeneration by targeting key functions of immune cells, muscle cells or both. Here we review the process of skeletal muscle regeneration with a special focus on the cross-talk between immune and muscle cells. We address the effect of aging on immune and skeletal muscle cells involved in muscle regeneration. Finally, the mechanisms of nutrient action on muscle regeneration are described, showing that quality of nutrition may help to preserve the capacity for skeletal muscle regeneration with age.

Vitamin D deficiency down-regulates Notch pathway contributing to skeletal muscle atrophy in old wistar rats.

BACKGROUND: The diminished ability of aged muscle to self-repair is a factor behind sarcopenia and contributes to muscle atrophy. Muscle repair depends on satellite cells whose pool size is diminished with aging. A reduction in Notch pathway activity may explain the age-related decrease in satellite cell proliferation, as this pathway has been implicated in satellite cell self-renewal. Skeletal muscle is a target of vitamin D which modulates muscle cell proliferation and differentiation in vitro and stimulates muscle regeneration in vivo. Vitamin D status is positively correlated to muscle strength/function, and elderly populations develop a vitamin D deficiency. The aim of this study was to evaluate how vitamin D deficiency induces skeletal muscle atrophy in old rats through a reduction in Notch pathway activity and proliferation potential in muscle. METHODS: 15-month-old male rats were vitamin D-depleted or not (control) for 9 months (n = 10 per group). Rats were 24-month-old at the end of the experiment. Gene and/or protein expression of markers of proliferation, or modulating proliferation, and of Notch signalling pathway were studied in the tibialis anterior muscle by qPCR and western blot. An unpaired student's t-test was performed to test the effect of the experimental conditions. RESULTS: Vitamin D depletion led to a drop in concentrations of plasma 25-hydroxyvitamin D in depleted rats compared to controls (-74%, p < 0.01). Tibialis anterior weight was decreased in D-depleted rats (-25%, p < 0.05). The D-depleted group showed -39%, -31% drops in expression of two markers known to modulate proliferation (Bmp4, Fgf-2 mRNA levels) and -56% drop in one marker of cell proliferation (PCNA protein expression) compared to controls (p < 0.05). Notch pathway activity was blunted in tibialis anterior of D-depleted rats compared to controls, seen as a down-regulation of cleaved Notch (-53%, p < 0.05) and its target Hes1 (-35%, p < 0.05). CONCLUSIONS: A 9-month vitamin D depletion induced vitamin D deficiency in old rats. Vitamin D depletion induces skeletal muscle atrophy in old rats through a reduction in Notch pathway activity and proliferation potential. Vitamin D deficiency could aggravate the age-related decrease in muscle regeneration capacity.