Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans

Abstract

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/m2) 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.

Mitochondrial DNA repair in aging and disease

“…Calorie restricted rodents have a longer lifespan than their ad libitum fed counterparts (85). A recent human trial showed that caloric restriction resulted in the expected reduction in body weight and blood insulin (86). Molecular analysis of this study revealed that caloric restriction and exercise increased the expression of genes involved in nutrient sensing and mitochondrial biogenesis.…”

“…Concurrently, caloric restriction decreased markers of oxidative stress. The authors suggest that caloric restriction induces biogenesis of "efficient" mitochondria as an adaptive mechanism, which in turn lowers oxidative stress (86). Dietary restriction has also been shown to be a modulator of membrane lipid peroxidation and cytosolic antioxidant status (87).…”

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

“…Increases in mitochondrial biogenesis and function have previously been shown to improve insulin sensitivity (Bonnard et al., 2008; Joseph, Adhihetty, & Leeuwenburgh, 2016). Furthermore, caloric restriction (CR), which is currently the only nutritional intervention that delays aging and extends lifespan in mammals, is known to stimulate mitochondrial metabolism (Civitarese et al., 2007; Lopez‐Lluch et al., 2006). Thus, we investigated the impacts of increased mitochondrial NAD levels on energy metabolism in Nmnat3 Tg mice.…”

“…In particular, mitochondria are a major source of free radicals including ROS, and it is accepted that mitochondrial dysfunction contributes considerably to the aging process (Bratic & Larsson, 2013; Murphy, 2009). It has also been shown that CR increases numbers of healthy mitochondria and promotes ATP production in rodents and humans (Civitarese et al., 2007). In addition, CR led to reduced oxygen consumption in mice, but efficient ATP production was maintained with decreased ROS generation (Guarente, 2008).…”

Effect of L-carnitine Supplementation on Nutritional Status and Physical Performance Under Calorie Restriction

“…The beneficial effects on glucoregulatory functions, improved insulin sensitivity have been seen in rodents and rhesus monkeys [5,6]. Studies have shown the effects of reduced caloric intake with a cut down on calories by 20-25 % of ad libitum fed subjects [7,8]. A few studies have reduced the intake by a fixed number of calories rather than a percentage of the regular intake.…”