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Nicotinamide and Sugar Metabolism Associated With Muscle Mass Loss During Calorie Restriction in Older Adults

ABSTRACT: Abstract Weight loss among older adults remains controversial due to lean mass loss and potential exacerbation of disability risk. Using the Medifast for Seniors clinical trial (NCT02730988), which investigated high protein supplementation (?1.0 g/kg/d) during caloric restriction to preserve lean mass among 96 older adults (>70 years, 74% women, 27% black) with obesity (BMI: 35 kg/m^2), we applied untargeted metabolomics to identify small molecules associated with the highly variable change in lean muscle mass during weight loss. Forty-seven participants were randomized to high protein weight loss, and 92% lost at least 5% body weight over 24 weeks. Across DXA-ascertained measures of lean body mass, gynoid lean mass exhibited the broadest range of change: +4% to -12%. For 38 participants, untargeted metabolomics data was generated from fasted serum samples collected before and after intervention. 121 serum metabolites were identified and change from baseline was tested for correlation with percent change in gynoid muscle mass. Increasing nicotinamide levels were associated with a greater loss of gynoid muscle mass (R^2=0.22, p=0.0027). Pathway analysis was applied to identify Kyoto Encyclopedia of Genes and Genomes (KEGG) biochemical pathways containing multiple nominally-associated metabolites. The amino sugar and nucleotide sugar metabolism pathway was significantly enriched (p=0.006), containing four sugar metabolites associated with shifts in lean muscle mass. This pathway is important in the glycosylation of polysaccharides, a ubiquitous and important regulator of energy metabolism, but has not previously been linked to muscle mass and should be further interrogated in preservation of lean muscle during weight loss.

SUBMITTER: Quillen E

PROVIDER: S-EPMC7741721 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundCaloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood.Methods and findingsThe current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 +/- 1.0 y), overweight (body mass index, 27.8 +/- 0.7 kg/m(2)) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, -135 +/- 42 kcal/d, p = 0.002 and CREX, -117 +/- 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% +/- 5% in the CR group (p = 0.005) and 21% +/- 4% in the CREX group (p < 0.004), with no change in the control group (2% +/- 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (-0.56 +/- 0.11 arbitrary units, p = 0.003) and CREX (-0.45 +/- 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR.ConclusionsThe observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults.

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Nicotinamide and Sugar Metabolism Associated With Muscle Mass Loss During Calorie Restriction in Older Adults

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