Skeletal muscle mitochondrial network dynamics in metabolic disorders and aging

With global demographics trending towards an aging population, the numbers of individuals with an age-associated loss of independence is increasing. A key contributing factor is loss of skeletal muscle mitochondrial, metabolic, and contractile function. Recent advances in imaging technologies have demonstrated the importance of mitochondrial morphology and dynamics in the pathogenesis of disease. In this review, we examine the evidence for altered mitochondrial dynamics as a mechanism in age and obesity-associated loss of skeletal muscle function, with a particular focus on the available human data. We highlight some of the areas where more data are needed to identify the specific mechanisms connecting mitochondrial morphology and skeletal muscle dysfunction

Mitochondrial oxidative DNA damage and exposure to particulate air pollution in mother-newborn pairs

Background: Studies emphasize the importance of particulate matter (PM) in the formation of reactive oxygen species and inflammation. We hypothesized that PM exposure during different time windows in pregnancy influences mitochondrial 8-hydroxy-2\u2032-deoxyguanosine (8-OHdG) levels, which is an established biomarker for oxidative stress, in both maternal and foetal blood. Methods: We investigated maternal (n = 224) and cord blood (n = 293) from mother-newborn pairs that were enrolled in the ENVIRONAGE birth cohort. We determined mitochondrial 8-OHdG by quantitative polymerase chain reaction (qPCR). Multivariable regression models were used to assess the association between mitochondrial 8-OHdG with PM10 and PM2.5 exposure over various time windows during pregnancy. Results: In multivariable analysis, PM10 exposure during the entire pregnancy was positively associated with levels of mitochondrial 8-OHdG in maternal blood. For an IQR increment in PM10 exposure an increase of 18.3 % (95 % confidence interval (CI): 5.6 to 33.4 %, p = 0.004) in 8-OHdG was observed. PM10 exposure during the last trimester of pregnancy was positively associated with levels of 8-OHdG (28.1, 95 % CI: 8.6 to 51.2 %, p = 0.004, for an IQR increment in PM10). In a similar way, PM2.5 exposure was significantly associated with an increase of mitochondrial 8-OHdG levels in maternal blood during the entire pregnancy (13.9, 95 % CI: 0.4 to 29.4 %, p = 0.04 for an IQR increment in PM2.5 exposure) and third trimester of pregnancy (28.1, 95 % CI: 3.6 to 58.4 %, p = 0.02 for an IQR increment in PM2.5 exposure). In umbilical cord blood, 8-OHdG levels were significantly associated with PM10 exposure during first and second trimester of pregnancy with respectively an increase of 23.0 % (95 % CI: 5.9 to 42.8 %, p = 0.007) and 16.6 % (95 % CI: 1.8 to 33.5 %, p = 0.03) for an IQR increment in PM10 exposure. Conclusions: We found PM-associated increased mitochondrial oxidative DNA damage during pregnancy in both mothers and their newborns. Accordingly, our study showed that particulate air pollution exposure in early life plays a role in increasing systemic oxidative stress, at the level of the mitochondria, both in mother and foetus

Adaptability to Balance Perturbations During Walking as a Potential Marker of Falls History in Older Adults

Given that falls most commonly occur during walking due to unexpected balance perturbations like trips and slips, walking-based balance assessment including walking stability and adaptability to such perturbations could be beneficial for fall risk assessment in older adults. This cross-sectional study reanalyzed data from two larger studies conducted with the same walking protocol. Participants completed unperturbed walking trials at speeds of 0.4 m/s up to 1.8 m/s in 0.2 m/s steps. Ten unannounced treadmill belt acceleration perturbations were then applied while participants walked at equivalent stability, assessed using the margins of stability. Retrospective (12 months) falls incidence was collected to divide participants into people with and without a history of falls. Twenty older adults (mean age 70.2 ± 2.9 years) were included in this analysis; eight people with one or more recent falls and 12 people without, closely matched by sex, age and height. No significant differences were found in unperturbed walking parameters or their variability. Overall perturbation-recovery step behavior differed slightly (not statistically significant) between the groups after the first perturbation and differences became more pronounced and significant after repetition of perturbations. The No-Falls group significantly reduced the number of recovery steps needed across the trials, whereas the Falls group did not show these improvements. People with a previous fall tended to have slightly delayed and more variable recovery responses after perturbation compared to non-fallers. Non-fallers demonstrate more signs of adaptability to repeated perturbations. Adaptability may give a broader indication of the ability of the locomotor system to respond and improve responses to sudden walking perturbations than unperturbed walking variability or recovery to a single novel perturbation. Adaptability may thus be a more useful marker of falls history in older adults and should be considered in further research

Older adults demonstrate interlimb transfer of reactive gait adaptations to repeated unpredictable gait perturbations

The ability to rapidly adjust gait to cope with unexpected mechanical perturbations declines with ageing. Previous studies however, have not ensured that gait stability pre-perturbation was equivalent across participants or age groups which may have influenced the outcomes. In this study, we investigate if age-related differences in stability following gait perturbations remain when all participants walk with equivalent stability. We also examine if interlimb transfer of gait adaptations are observed in healthy older adults, by examining if adaptation to repeated perturbations of one leg can benefit stability recovery when the other leg is perturbed. 30 young and 28 older healthy adults experienced ten unpredictable treadmill belt accelerations (the first and last applied to the right leg, the others to the left leg) during walking at their stability-normalised walking speeds (young: 1.32±0.07m/s; older: 1.31±0.13m/s; normalised to an average margin of stability of 0.05m). Using kinematic data, we assessed the margins of stability during unperturbed walking and the first eight post-perturbation recovery steps. Older adults required three more steps to recover during the first perturbation to each leg than the young adults. Yet, after repeated perturbations of the left leg, older adults required only one more step to recover. Interestingly, for the untrained right leg, the older adults could regain stability with three fewer steps, indicating interlimb transfer of the improvements. Age differences in reactive gait stability remain even when participants’ walk with equivalent stability. Furthermore, we show that healthy older adults can transfer improvements in balance recovery made during repeated perturbations to one limb to their recovery following a perturbation to the untrained limb

Skeletal muscle mitochondrial network dynamics in metabolic disorders and aging

With global demographics trending towards an aging population, the numbers of individuals with an age-associated loss of independence is increasing. A key contributing factor is loss of skeletal muscle mitochondrial, metabolic, and contractile function. Recent advances in imaging technologies have demonstrated the importance of mitochondrial morphology and dynamics in the pathogenesis of disease. In this review, we examine the evidence for altered mitochondrial dynamics as a mechanism in age and obesity-associated loss of skeletal muscle function, with a particular focus on the available human data. We highlight some of the areas where more data are needed to identify the specific mechanisms connecting mitochondrial morphology and skeletal muscle dysfunction

Epigenetics applied to epidemiology: investigating environmental factors and lifestyle influence on human health

Epigenetics modifications, that include variations in DNA methylation, histone acetylation and micro RNA (miRNA) expression, co-operate together, influencing genome expression and function, in response to exogenous stimuli or exposures. Thus, epigenetic tools applied to epidemiology are useful in investigating, at the population level, the relationships between exposures to environmental, lifestyle, genetic, socioeconomic risk factors, and the epigenome, and/or specific health outcomes. But the choice of an appropriate study design and of valid epidemiological methods has a key role in determining the achievement of the study. This review summarises available evidence about the role of the most investigated epigenetic mechanisms in mediating lifestyle or environmental exposure effects on human health, considering the entire life-course, from in-utero to adulthood. Moreover, we illustrate the most important variables that should be properly considered when designing an epigenetic epidemiology study: the choice of an appropriate study design, a proper estimation of the required sample size, a correct biological sample selection, a validation strategy for epigenetics data, and an integrated exposure assessment methodology

Healthy aging and muscle function are positively associated with NAD(+) abundance in humans

Skeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD(+)) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD(+) levels that were more similar to those found in younger individuals. NAD(+) abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD(+) and health status in human aging

Healthy aging and muscle function are positively associated with NAD+ abundance in humans

Skeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD+) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD+ levels that were more similar to those found in younger individuals. NAD+ abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD+ and health status in human aging

NAD+-Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults

BACKGROUND: Boosting NAD(+) via supplementation with niacin equivalents has been proposed as a potential modality capable of promoting healthy aging and negating age-dependent declines of skeletal muscle mass and function. OBJECTIVES: We investigated the efficacy of NAD(+)-precursor supplementation (tryptophan, nicotinic acid, and nicotinamide) on skeletal muscle mitochondrial function in physically compromised older adults. METHODS: A randomized, double-blind, controlled trial was conducted in 14 (female/male: 4/10) community-dwelling, older adults with impaired physical function [age, 72.9 ± 4.0 years; BMI, 25.2 ± 2.3 kg/m(2)]. Participants were supplemented with 207.5 mg niacin equivalents/day [intervention (INT)] and a control product (CON) that did not contain niacin equivalents, each for 32 days. The primary outcomes tested were mitochondrial oxidative capacity and exercise efficiency, analyzed by means of paired Student's t-tests. Secondary outcomes, such as NAD(+) concentrations, were analyzed accordingly. RESULTS: Following supplementation, skeletal muscle NAD(+) concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD(+)-precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD(+) metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD(+)-precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. CONCLUSIONS: Our findings are consistent with previous findings on NAD(+) efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD(+)-precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034

OUP accepted manuscript

BACKGROUND: Boosting NAD(+) via supplementation with niacin equivalents has been proposed as a potential modality capable of promoting healthy aging and negating age-dependent declines of skeletal muscle mass and function. OBJECTIVES: We investigated the efficacy of NAD(+)-precursor supplementation (tryptophan, nicotinic acid, and nicotinamide) on skeletal muscle mitochondrial function in physically compromised older adults. METHODS: A randomized, double-blind, controlled trial was conducted in 14 (female/male: 4/10) community-dwelling, older adults with impaired physical function [age, 72.9 ± 4.0 years; BMI, 25.2 ± 2.3 kg/m(2)]. Participants were supplemented with 207.5 mg niacin equivalents/day [intervention (INT)] and a control product (CON) that did not contain niacin equivalents, each for 32 days. The primary outcomes tested were mitochondrial oxidative capacity and exercise efficiency, analyzed by means of paired Student's t-tests. Secondary outcomes, such as NAD(+) concentrations, were analyzed accordingly. RESULTS: Following supplementation, skeletal muscle NAD(+) concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD(+)-precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD(+) metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD(+)-precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. CONCLUSIONS: Our findings are consistent with previous findings on NAD(+) efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD(+)-precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034