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1.  Analytes and Metabolites Associated with Muscle Quality in Young, Healthy Adults 
Identification of mechanisms that underlie lower extremity muscle quality (leg press one repetition maximum/total lean mass; LP/Lean) may be important for individuals interested in optimizing fitness and sport performance. The purpose of the current study was to provide observational insight into mechanisms that may underlie muscle quality by characterizing the association between 286 mass spectrometry metabolites and 17 chemistry screen analytes with LP/Lean in young, healthy adults (N = 77 (49 women and 28 men); mean age, 24.4 ± 4.2 yr; BMI, 23.5 ± 2.6 kg·m−2).
Principal components analysis (PCA) was used to reduce the 286 metabolites into 73 metabolite-containing PCA factors. Sex-adjusted linear regression was used to examine the association between PCA factors and chemistry screen analytes with LP/Lean. Q values were computed to account for multiple comparison testing. Stepwise linear regression and leave-one-out cross validation were used to identify a predictor set representative of LP/Lean and to assess internal validity, respectively.
Metabolites or analytes related to dietary protein intake (albumin, branched-chain amino acids (BCAA)) and excitation-contraction coupling (calcium and magnesium) were positively associated, whereas metabolites related to gut bacterial metabolism (cinnamoylglycine, hydrocinnamate, hippurate, indolepropionate) and peroxisome proliferator–activated receptor-alpha (PPAR-α) (methylglutarylcarnitine and cinnamoylglycine) activation were negatively associated with LP/Lean. Use of leave-one-out cross validation identified magnesium, sex, and the PCA factors containing BCAAs and methionine and methylglutarylcarnitine to be present in more than 90% of the stepwise regression models, thereby explaining 26.7% of the variance (adjusted R2) inherent in muscle quality.
Collectively, these data suggest that mechanisms related to dietary protein intake, excitation-contraction coupling, gut microbial metabolism, and PPAR-α activation may underlie lower extremity muscle quality in young, healthy adults.
PMCID: PMC4862366  PMID: 25412292
2.  Branched Chain Amino Acids Are Associated With Muscle Mass in Functionally Limited Older Adults 
Metabolic profiling may provide insight into biologic mechanisms related to the maintenance of muscle and fat-free mass in functionally limited older adults. The objectives of the study were to characterize the association between thigh muscle cross-sectional area (CSA) and the fat-free mass index (FFMI; total lean mass/height2) with the serum metabolite profile, to further identify significant metabolites as associated with markers of insulin resistance or inflammation, and to develop a metabolite predictor set representative of muscle CSA and the FFMI in functionally limited older adults.
Multivariable-adjusted linear regression was used on mass spectrometry-based metabolomic data to determine significant associations between serum metabolites with muscle CSA and the FFMI in 73 functionally limited (Short Physical Performance Battery ≤ 10) older adults (age range: 70–85 years). Significant metabolites were further examined for associations with markers of insulin resistance (homeostasis model assessment of insulin resistance) or inflammation (tumor necrosis factor-α and interleukin-6). Multivariable-adjusted stepwise regression was used to develop a metabolite predictor set representative of muscle CSA and the FFMI.
Seven branched chain amino acid-related metabolites were found to be associated with both muscle CSA and the FFMI. Separately, two metabolites were identified as insulin resistance-associated markers of the FFMI, whereas four metabolites were identified as inflammation-associated markers of either muscle CSA or the FFMI. Stepwise models identified combinations of metabolites to explain approximately 68% of the variability inherent in muscle CSA or the FFMI.
Collectively, we report multiple branched chain amino acids and novel inflammation-associated tryptophan metabolites as markers of muscle CSA or the FFMI in functionally limited older adults.
PMCID: PMC4073623  PMID: 24085401
Biomarkers; Inflammation; Muscle; Insulin resistance; Metabolomics.
3.  Metabolites related to gut bacterial metabolism, peroxisome proliferator-activated receptor-alpha activation, and insulin sensitivity are associated with physical function in functionally-limited older adults 
Aging Cell  2014;13(5):918-925.
Identification of mechanisms underlying physical function will be important for addressing the growing challenge that health care will face with physical disablement in the expanding aging population. Therefore, the goals of the current study were to use metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6-month change in serum mass spectrometry-obtained amino acids, fatty acids, and acylcarnitines with baseline and the 6-month change in muscle strength (leg press one repetition maximum divided by total lean mass, LP/Lean), lower extremity function [short physical performance battery (SPPB)], and mobility (400 m gait speed, 400-m), in response to 6 months of a combined resistance exercise and nutritional supplementation (whey protein or placebo) intervention in functionally-limited older adults (SPPB ≤ 10; 70–85 years, N = 73). Metabolites related to gut bacterial metabolism (cinnamoylglycine, phenol sulfate, p-cresol sulfate, 3-indoxyl sulfate, serotonin, N-methylproline, hydrocinnamate, dimethylglycine, trans-urocanate, valerate) that are altered in response to peroxisome proliferator-activated receptor-alpha (PPAR-α) activation (α-hydroxyisocaproate, α-hydroxyisovalerate, 2-hydroxy-3-methylvalerate, indolelactate, serotonin, 2-hydroxypalmitate, glutarylcarnitine, isobutyrylcarnitine, cinnamoylglycine) and that are related to insulin sensitivity (monounsaturated fatty acids: 5-dodecenoate, myristoleate, palmitoleate; γ-glutamylamino acids: γ-glutamylglutamine, γ-glutamylalanine, γ-glutamylmethionine, γ-glutamyltyrosine; branched-chain amino acids: leucine, isoleucine, valine) were associated with function at baseline, with the 6-month change in function or were identified in backward elimination regression predictive models. Collectively, these data suggest that gut microbial metabolism, PPAR-α activation, and insulin sensitivity may be involved in mechanisms that underlie physical function in functionally-limited older adults.
PMCID: PMC4331755  PMID: 25041144
aging; gut bacterial metabolites; insulin sensitivity; metabolomics; peroxisome proliferator-activated receptor-alpha; physical function
4.  Increased mitochondrial matrix directed superoxide production by fatty acid hydroperoxides in skeletal muscle mitochondria 
Free radical biology & medicine  2010;50(5):592-601.
Previous studies have shown that muscle atrophy is associated with mitochondrial dysfunction and an increased rate of mitochondrial reactive oxygen species production. We recently demonstrated that fatty acid hydroperoxides (FA-OOH) are significantly elevated in mitochondria isolated from atrophied muscles. The purpose of the current study is to determine whether FA-OOH can alter skeletal muscle mitochondrial function. We found that FA-OOH (at low micromolar concentrations) induces mitochondrial dysfunction assessed by decrease in the rate of ATP production, oxygen consumption and activity of respiratory chain complexes I and III. Using methods to distinguish superoxide release towards the matrix and inter-membrane space, we demonstrate that FA-OOH significantly elevates oxidative stress in the mitochondrial matrix (and not the inter-membrane space) with complex I as the major site of superoxide production (most likely from a site upstream of the ubiquinone binding site but downstream from the flavin binding site-the iron sulfur clusters). Our results are the first to indicate that FA-OOH’s are important modulators of mitochondrial function and oxidative stress in skeletal muscle mitochondria and may play an important role in muscle atrophies that are associated with increased generation of FA-OOH’s, e.g., denervation-induced muscle atrophy.
PMCID: PMC4017321  PMID: 21172427
Oxidative stress; superoxide; fatty acid hydroperoxides; hydrogen peroxide; mitochondria
5.  Serum Glycine Is Associated with Regional Body Fat and Insulin Resistance in Functionally-Limited Older Adults 
PLoS ONE  2013;8(12):e84034.
Metabolic profiling may provide insight into biologic mechanisms related to age-related increases in regional adiposity and insulin resistance.
The objectives of the current study were to characterize the association between mid-thigh intermuscular and subcutaneous adipose tissue (IMAT, SCAT, respectively) and, abdominal adiposity with the serum metabolite profile, to identify significant metabolites as further associated with the homeostasis model assessment of insulin resistance (HOMA-IR), and, to develop a HOMA-IR associated metabolite predictor set representative of regional adiposity, in 73 functionally-limited (short physical performance battery ≤10; SPPB) older adults (age range, 70–85 y).
Fasting levels of 181 total metabolites, including amino acids, fatty acids and acylcarnitines were measured with use of an untargeted mass spectrometry-based metabolomic approach. Multivariable-adjusted linear regression was used in all analyses.
Thirty-two, seven and one metabolite(s) were found to be associated with IMAT, abdominal adiposity and, SCAT, respectively, including the amino acid glycine, which was positively associated with SCAT and, negatively associated with both IMAT and abdominal adiposity. Glycine and four metabolites found to be significantly associated with regional adiposity were additionally associated with HOMA-IR. Separate stepwise regression models identified glycine as a HOMA-IR associated marker of both IMAT (model R2 = 0.51, p<0.0001) and abdominal adiposity (model R2 = 0.41, p<0.0001).
Our findings for a positive association between glycine with SCAT but, a negative association between glycine with IMAT and abdominal adiposity supports the hypothesis that SCAT metabolic processes are different from that found in other fat depots. In addition, because of the significant associations found between glycine with HOMA-IR, IMAT, SCAT and abdominal adiposity, our results suggest glycine as a serum biomarker of both insulin sensitivity and regional fat mass in functionally-limited older adults.
PMCID: PMC3877144  PMID: 24391874
6.  Dietary restriction attenuates age-associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD 
Aging cell  2012;11(5):770-782.
Age-related loss of muscle mass and function, sarcopenia, has a major impact on the quality of life in the elderly. Among the proposed causes of sarcopenia are mitochondrial dysfunction and accumulated oxidative damage during aging. Dietary restriction (DR), a robust dietary intervention that extends lifespan and modulates age-related pathology in a variety of species has been shown to protect from sarcopenia in rodents. Although the mechanism(s) by which DR modulates aging are still not defined, one potential mechanism is through modulation of oxidative stress and mitochondrial dysfunction. To directly test the protective effect of DR against oxidative stress induced muscle atrophy in vivo, we subjected mice lacking a key antioxidant enzyme, CuZnSOD (Sod1) to DR (40% of ad libitum fed diet). We have previously shown that the Sod1−/− mice exhibit an acceleration of sarcopenia associated with high oxidative stress, mitochondrial dysfunction, and severe neuromuscular innervation defects. Despite the dramatic atrophy phenotype in the Sod1−/− mice, DR led to a reversal or attenuation of reduced muscle function, loss of innervation and muscle atrophy in these mice. DR improves mitochondrial function as evidenced by enhanced Ca2+ regulation and reduction of mitochondrial reactive oxygen species (ROS). Furthermore, we show upregulation of SIRT3 and MnSOD in DR animals, consistent with reduced mitochondrial oxidative stress and reduced oxidative damage in muscle tissue measured as F2- isoprostanes. Collectively, our results demonstrate that DR is a powerful mediator of mitochondrial function, mitochondrial ROS production, and oxidative damage, providing a solid protection against oxidative stress induced neuromuscular defects and muscle atrophy in vivo even under conditions of high oxidative stress.
PMCID: PMC3444532  PMID: 22672615
7.  Complex I generated, mitochondrial matrix-directed superoxide is released from the mitochondria through voltage dependent anion channels 
Mitochondrial complex I has previously been shown to release superoxide exclusively towards the mitochondrial matrix, whereas complex III releases superoxide to both the matrix and the cytosol. Superoxide produced at Complex III has been shown to exit the mitochondria through voltage dependent anion channels (VDAC). To test whether complex I-derived, mitochondrial matrix-directed superoxide can be released to the cytosol, we measured superoxide generation in mitochondria isolated from wild type and from mice genetically altered to be deficient in MnSOD activity (TnIFastCreSod2fl/fl). Under experimental conditions that produce superoxide primarily by complex I (glutamate/malate plus rotenone, GM+R), MnSOD-deficient mitochondria release ~4-fold more superoxide than mitochondria isolated from wild type mice. Exogenous CuZnSOD completely abolished the EPR-derived GM+R signal in mitochondria isolated from both genotypes, evidence that confirms mitochondrial superoxide release. Addition of the VDAC inhibitor DIDS significantly reduced mitochondrial superoxide release (~75%) in mitochondria from either genotype respiring on GM+R. Conversely, inhibition of potential inner membrane sites of superoxide exit, including the matrix face of the mitochondrial permeability transition pore and the inner membrane anion channel did not reduce mitochondrial superoxide release in the presence of GM+R in mitochondria isolated from either genotype. These data support the concept that complex I-derived mitochondrial superoxide release does indeed occur and that the majority of this release occurs through VDACs.
PMCID: PMC3400138  PMID: 22613204
mitochondria; superoxide; voltage dependent anion channels
8.  Loss of manganese superoxide dismutase leads to abnormal growth and signal transduction in mouse embryonic fibroblasts 
Free radical biology & medicine  2010;49(8):1255-1262.
Manganese superoxide dismutase (MnSOD) in the mitochondria plays an important role in cellular defense against oxidative damage. Homozygous MnSOD knockout (Sod2−/−) mice are neonatal lethal, indicating the essential role of MnSOD in early development. To investigate the potential cellular abnormalities underlying the aborted development of Sod2−/− mice, we examined the growth of isolated mouse embryonic fibroblasts (MEF) from Sod2−/− mice. We found that the proliferation of Sod2−/− MEFs was significantly decreased when compared with wild type MEFs despite the absence of morphological differences. The Sod2−/− MEFs produced less cellular ATP, had lower O2 consumption, generated more superoxide, and expressed less Prdx3 protein. Furthermore, the loss of MnSOD dramatically altered several markers involved in cell proliferation and growth, including decreased growth stimulatory function of mTOR signaling and enhanced growth inhibitory function of GSK-3β signaling. Interestingly, the G protein coupled receptor-mediated intracellular Ca2+ ([Ca2+]i) signal transduction was also severely suppressed in Sod2−/− MEFs. Finally, the ratio of LC3-II/LC3-I, an index of autophagic activity, was increased in Sod2−/− MEFs, consistent with a reduction of mTOR signal transduction. These data demonstrate that MnSOD deficiency results in alterations in several key signaling pathways, which may contribute to the lethal phenotype of Sod2−/− mice.
PMCID: PMC3418666  PMID: 20638473
MnSOD; oxidative stress; ROS; signal transduction
9.  MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging 
Aging cell  2011;10(3):493-505.
In a previous study, we reported that a deficiency in MnSOD activity (approximately 80% reduction) targeted to type IIB skeletal muscle fibers was sufficient to elevate oxidative stress and to reduce muscle function in young adult mice (TnIFastCreSod2fl/fl mice). In the present study, we used TnIFastCreSod2fl/fl mice to examine the effect of elevated oxidative stress on mitochondrial function and to test the hypothesis that elevated oxidative stress and decreased mitochondrial function over the lifespan of the TnIFastCreSod2fl/fl mice would be sufficient to accelerate muscle atrophy associated with aging. We found that mitochondrial function is reduced in both young and old TnIFastCreSod2fl/fl mice, when compared with control mice. Complex II activity is reduced by 47% in young and by ~90% in old TnIFastCreSod2fl/fl mice, associated with reduced levels of the catalytic subunits for complex II, SDHA and SDHB. Complex II-linked mitochondrial respiration is reduced by approximately 70% in young TnIFastCreSod2fl/fl mice. Complex II-linked mitochondrial ATP production is reduced by 39% in young and was found to be almost completely absent in old TnIFastCreSod2fl/fl mice. Furthermore, in old TnIFastCreSod2fl/fl mice, aconitase activity is almost completely abolished; mitochondrial superoxide release remains greater than 2-fold elevated; and oxidative damage (measured as F2 isoprostanes) is increased by 30% relative to age-matched controls. These data show that despite elevated skeletal muscle-specific mitochondrial oxidative stress, oxidative damage and complex II-linked mitochondrial dysfunction, age-related muscle atrophy was not accelerated in old TnIFastCreSod2fl/fl mice, suggesting mitochondrial oxidative stress may not be causal for age-related muscle atrophy.
PMCID: PMC3094473  PMID: 21385310
10.  Overexpression of Mn Superoxide Dismutase Does Not Increase Life Span in Mice 
Genetic manipulations of Mn superoxide dismutase (MnSOD), SOD2 expression have demonstrated that altering the level of MnSOD activity is critical for cellular function and life span in invertebrates. In mammals, Sod2 homozygous knockout mice die shortly after birth, and alterations of MnSOD levels are correlated with changes in oxidative damage and in the generation of mitochondrial reactive oxygen species. In this study, we directly tested the effects of overexpressing MnSOD in young (4–6 months) and old (26–28 months) mice on mitochondrial function, levels of oxidative damage or stress, life span, and end-of-life pathology. Our data show that an approximately twofold overexpression of MnSOD throughout life in mice resulted in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related decline in mitochondrial ATP production. However, this change in MnSOD expression did not alter either life span or age-related pathology.
PMCID: PMC2759571  PMID: 19633237
Oxidative damage; Mn superoxide dismutase; Pathology; Aging

Results 1-10 (10)