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Heterogeneous effects of old age on human muscle oxidative capacity in vivo: a systematic review and meta-analysis.
Fitzgerald, LF, Christie, AD, Kent, JA
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2016;(11):1137-1145
Abstract
Despite intensive efforts to understand the extent to which skeletal muscle mitochondrial capacity changes in older humans, the answer to this important question remains unclear. To determine what the preponderance of evidence from in vivo studies suggests, we conducted a systematic review and meta-analysis of the effects of age on muscle oxidative capacity as measured noninvasively by magnetic resonance spectroscopy. A secondary aim was to examine potential moderators contributing to differences in results across studies, including muscle group, physical activity status, and sex. Candidate papers were identified from PubMed searches (n = 3561 papers) and the reference lists of relevant papers. Standardized effects (Hedges' g) were calculated for age and each moderator using data from the 22 studies that met the inclusion criteria (n = 28 effects). Effects were coded as positive when older (age, ≥55 years) adults had higher muscle oxidative capacity than younger (age, 20-45 years) adults. The overall effect of age on oxidative capacity was positive (g = 0.171, p < 0.001), indicating modestly greater oxidative capacity in old. Notably, there was significant heterogeneity in this result (Q = 245.8, p < 0.001; I2 = ∼70%-90%). Muscle group, physical activity, and sex were all significant moderators of oxidative capacity (p ≤ 0.029). This analysis indicates that the current body of literature does not support a de facto decrease of in vivo muscle oxidative capacity in old age. The heterogeneity of study results and identification of significant moderators provide clarity regarding apparent discrepancies in the literature, and indicate the importance of accounting for these variables when examining purported age-related differences in muscle oxidative capacity.
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Contribution of the Mitochondria to Locomotor Muscle Dysfunction in Patients With COPD.
Taivassalo, T, Hussain, SN
Chest. 2016;(5):1302-12
Abstract
COPD is a significant public health challenge, notably set to become the third leading cause of death and fifth leading cause of chronic disability worldwide by the next decade. Skeletal muscle impairment is now recognized as a disabling, extrapulmonary consequence of COPD that is associated with reduced quality of life and premature mortality. Because COPD typically manifests in older individuals, these clinical features may overlie normal age-associated declines in muscle function and performance. Although physical inactivity, oxidative stress, inflammation, hypoxia, malnutrition, and medications all likely contribute to this comorbidity, a better understanding of the underlying mechanism is needed to develop effective therapies. Mitochondrial alterations have been described; these alterations include reductions in density and oxidative enzyme activity, increased mitochondrial reactive oxygen species production, and induction of muscle proteolysis including autophagy. This review focuses on the perspective that mitochondrial alterations contribute to impaired locomotor muscle performance in patients with COPD by reducing oxidative capacity and thus endurance, as well as by triggering proteolysis and thus contributing to atrophy and weakness. We discuss how the potential underlying mechanisms converge on mitochondria by targeting the peroxisome proliferator-activated receptor γ-coactivator-1α signaling pathway (thereby reducing mitochondrial biogenesis and muscle oxidative capacity and potentially increasing fiber atrophy) and how taking advantage of normal muscle plasticity and mitochondrial biogenesis may reverse this pathophysiology. We propose recent therapeutic strategies aimed at increasing peroxisome proliferator-activated receptor γ-coactivator-1α levels, such as endurance training and exercise mimetic drugs, with the strong rationale for increasing mitochondrial biogenesis and function and thus improving the muscle phenotype in COPD.
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Physical inactivity and muscle oxidative capacity in humans.
Gram, M, Dahl, R, Dela, F
European journal of sport science. 2014;(4):376-83
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Abstract
Physical inactivity is associated with a high prevalence of type 2 diabetes and is an independent predictor of mortality. It is possible that the detrimental effects of physical inactivity are mediated through a lack of adequate muscle oxidative capacity. This short review will cover the present literature on the effects of different models of inactivity on muscle oxidative capacity in humans. Effects of physical inactivity include decreased mitochondrial content, decreased activity of oxidative enzymes, changes in markers of oxidative stress and a decreased expression of genes and contents of proteins related to oxidative phosphorylation. With such a substantial down-regulation, it is likely that a range of adenosine triphosphate (ATP)-dependent pathways such as calcium signalling, respiratory capacity and apoptosis are affected by physical inactivity. However, this has not been investigated in humans, and further studies are required to substantiate this hypothesis, which could expand our knowledge of the potential link between lifestyle-related diseases and muscle oxidative capacity. Furthermore, even though a large body of literature reports the effect of physical training on muscle oxidative capacity, the adaptations that occur with physical inactivity may not always be opposite to that of physical training. Thus, it is concluded that studies on the effect of physical inactivity per se on muscle oxidative capacity in functional human skeletal muscle are warranted.
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The impact of severe burns on skeletal muscle mitochondrial function.
Porter, C, Herndon, DN, Sidossis, LS, Børsheim, E
Burns : journal of the International Society for Burn Injuries. 2013;(6):1039-47
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Abstract
Severe burns induce a pathophysiological response that affects almost every physiological system within the body. Inflammation, hypermetabolism, muscle wasting, and insulin resistance are all hallmarks of the pathophysiological response to severe burns, with perturbations in metabolism known to persist for several years post injury. Skeletal muscle is the principal depot of lean tissue within the body and as the primary site of peripheral glucose disposal, plays an important role in metabolic regulation. Following a large burn, skeletal muscle functions as and endogenous amino acid store, providing substrates for more pressing functions, such as the synthesis of acute phase proteins and the deposition of new skin. Subsequently, burn patients become cachectic, which is associated with poor outcomes in terms of metabolic health and functional capacity. While a loss of skeletal muscle contractile proteins per se will no doubt negatively impact functional capacity, detriments in skeletal muscle quality, i.e. a loss in mitochondrial number and/or function may be quantitatively just as important. The goal of this review article is to summarise the current understanding of the impact of thermal trauma on skeletal muscle mitochondrial content and function, to offer direction for future research concerning skeletal muscle mitochondrial function in patients with severe burns, and to renew interest in the role of these organelles in metabolic dysfunction following severe burns.
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Mitochondrial function and insulin resistance during aging: a mini-review.
Phielix, E, Szendroedi, J, Roden, M
Gerontology. 2011;(5):387-96
Abstract
BACKGROUND Insulin resistance, i.e. impaired insulin sensitivity, and type 2 diabetes are more prevalent in elderly humans. Both conditions relate to lower aerobic performance and increased body fatness, which have been linked to reduced mitochondrial oxidative capacity. Thus, lower insulin sensitivity in the elderly could result from age-related diminished energy metabolism or from lifestyle-related abnormalities. OBJECTIVE This review addresses the question whether insulin sensitivity and mitochondrial oxidative capacity are independently affected during aging and type 2 diabetes. METHODS Only studies were analyzed which included elderly persons and employed state-of-the-art methodology to assess insulin sensitivity and oxidative capacity, e.g. electron microscopic imaging, in vivo magnetic resonance spectroscopy or ex vivo high-resolution respirometry. RESULTS Humans with or at risk of type 2 diabetes frequently exhibit insulin resistance along with structural and functional abnormalities of muscular mitochondria. Low mitochondrial oxidative capacity causes muscular fat accumulation, which impedes insulin signaling via lipid intermediates, in turn affecting oxidative capacity. However, insulin sensitivity is not generally reduced with age, when groups are carefully matched for physical activity and body fatness. Moreover, lifestyle intervention studies revealed discordant responses of mitochondrial oxidative capacity and insulin sensitivity. CONCLUSIONS In the elderly, low mitochondrial oxidative capacity likely results from age-related effects acquired during life span. Insulin resistance occurs independently of age mostly due to unhealthy lifestyle on top of genetic predisposition. Thus, insulin sensitivity and mitochondrial function may not be causally related, but mutually amplify each other during aging.
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Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging.
Ljubicic, V, Joseph, AM, Saleem, A, Uguccioni, G, Collu-Marchese, M, Lai, RY, Nguyen, LM, Hood, DA
Biochimica et biophysica acta. 2010;(3):223-34
Abstract
Acute contractile activity of skeletal muscle initiates the activation of signaling kinases. This promotes the phosphorylation of transcription factors, leading to enhanced DNA binding and transcriptional activation and/or repression. The mRNA products of nuclear genes encoding mitochondrial proteins are translated in the cytosol and imported into pre-existing mitochondria. When contractile activity is repeated, the recapitulation of these cellular events progressively leads to an expansion of the mitochondrial reticulum within muscle. This has physiologically relevant health benefit, including enhanced lipid metabolism and reduced muscle fatigability. In aging skeletal muscle, the response to contractile activity appears to be attenuated, suggesting that a greater contractile stimulus is required to attain a similar phenotype adaptation. This review summarizes our current understanding of the effects of exercise on the gene expression pathway leading to organelle biogenesis in muscle.
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Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals.
Holloway, GP, Bonen, A, Spriet, LL
The American journal of clinical nutrition. 2009;(1):455S-62S
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A reduction in fatty acid (FA) oxidation has been associated with lipid accumulation and insulin resistance in skeletal muscle of obese individuals. Numerous reports suggest that the reduction in FA oxidation may result from intrinsic mitochondrial defects, although little direct evidence has been offered to support this conclusion. This brief review summarizes recent work from our laboratory that reexamined whether this decrease in skeletal muscle FA oxidation with obesity was attributable to a dysfunction in FA oxidation within mitochondria or simply to a reduction in muscle mitochondrial content. Whole-muscle mitochondrial content and FA oxidation was reduced in the obese, but there was no decrease in the ability of isolated mitochondria to oxidize FA. The mitochondrial content of the transport protein, FA translocase (FAT/CD36), did not differ between lean and obese women but was correlated with mitochondrial FA oxidation. It was concluded that the reduced FA oxidation in obesity is attributable to decreased muscle mitochondrial content and not intrinsic defects in mitochondrial FA oxidation, and that mitochondrial FAT/CD36 is involved in regulating FA oxidation in human skeletal muscle. The reduced skeletal muscle mitochondrial content with obesity may result from impaired mitochondrial biogenesis. However, this did not result from decreased protein contents of various transcription factors, because peroxisome proliferater-activated receptor gamma coactivator 1alpha (PGC1alpha), PGC1beta, peroxisome proliferator-activated receptor alpha (PPARalpha), and mitochondrial transcription factor A (TFAM) were not reduced with obesity. In contrast, it appears that obesity is associated with altered regulation of cofactors (PGC1alpha and PGC1beta) and their downstream transcription factors (PPARalpha, PPARdelta/beta, and TFAM), because relations among these variables were present in muscle from lean individuals but not from obese individuals. These findings imply that obese individuals would benefit from interventions that increase the skeletal muscle mitochondrial content and the potential for oxidizing FAs.
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Muscle mitochondrial function in patients with type 2 diabetes mellitus and peripheral arterial disease: implications in vascular surgery.
Pedersen, BL, Baekgaard, N, Quistorff, B
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2009;(3):356-64
Abstract
OBJECTIVES (1) To review the available information on mitochondrial function in type 2 diabetes mellitus (T2DM) and peripheral arterial disease (PAD) obtained by non-invasive phosphorus magnetic resonance spectroscopy ((31)PMRS), near-infrared spectroscopy (NIRS) in vivo and respirometry on mitochondria isolated from muscle biopsies in vitro (2) to evaluate the usefulness of such data in the diagnosis, treatment and prognosis of these patients. DESIGN Review. SEARCH STRATEGY PubMed (http://www.ncbi.nlm.nih.gov/PubMed) and manual literature search. MAIN RESULTS Fifty-three articles were retrieved, which included (31)PMRS, 15, NIRS, 11, Combined, 1 and Respirometry, 2 and background literature, 24. CONCLUSION Muscle mitochondrial function is impaired in both T2DM and PAD patients, but differently. Patients suffering from both pathological conditions will display more serious impairment of the mitochondrial function. Mitochondrial function and the degree of ischaemic disease as evaluated by (31)PMRS and NIRS are well correlated. The NIRS technique appears to determine the degree of PAD better than (31)PMRS. It is argued that systematic testing of mitochondrial function may be a useful prognostic tool with PAD and T2DM, but clinical studies are needed.
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Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance.
Holloszy, JO
The American journal of clinical nutrition. 2009;(1):463S-6S
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Abstract
Patients with type 2 diabetes, insulin-resistant obese individuals, and insulin-resistant offspring of patients with diabetes have approximately 30% less mitochondria in their skeletal muscles than age-matched healthy controls. It has been hypothesized that this "deficiency" of mitochondria mediates insulin resistance by impairing the ability of muscle to oxidize fatty acids (FAs). However, a 30% decrease in mitochondria should not impair the ability of muscle to oxidize FAs because the capacity of muscle to oxidize substrate is far in excess of what is needed to supply energy in the basal state, ie, in resting muscle. In pathologic states in which mitochondrial content/function is so severely impaired as to limit substrate oxidation in resting muscle, glucose uptake and insulin action are actually enhanced. Recent studies have shown that feeding rodents high-fat diets and raising FA concentrations results in muscle insulin resistance despite an increase muscle mitochondria that enhances the capacity for fat oxidation. Furthermore, it was recently shown that skeletal muscle mitochondrial capacity for oxidative phosphorylation in Asian Indians with type 2 diabetes is the same as in nondiabetic Indians and higher than in healthy European Americans. In light of this evidence, it seems highly unlikely that "mitochondrial deficiency" causes muscle insulin resistance.
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Contribution of FAT/CD36 to the regulation of skeletal muscle fatty acid oxidation: an overview.
Holloway, GP, Luiken, JJ, Glatz, JF, Spriet, LL, Bonen, A
Acta physiologica (Oxford, England). 2008;(4):293-309
Abstract
Long chain fatty acids (LCFAs) are an important substrate for ATP production within the skeletal muscle. The process of LCFA delivery from adipose tissue to muscle mitochondria involves many regulatory steps. Recently, it has been recognized that LCFA oxidation is not only dependent on LCFA delivery to the muscle, but also on regulatory steps within the muscle. Increasing selected fatty acid binding proteins/transporters on the plasma membrane facilitates a very rapid LCFA increase into the muscle, independent of any changes in LCFA delivery to the muscle. Such a mechanism of LCFA transporter translocation is activated by muscle contraction. Intramuscular triacylglycerols may also be hydrolysed to provide fatty acids for mitochondrial oxidation, particularly during exercise, when hormone-sensitive lipase and other enzymes are activated. Mitochondrial LCFA entry is also highly regulated. This however does not involve only the malonyl CoA carnitine palmitoyltransferase-I (CPTI) axis. Exercise-induced fatty acid entry into mitochondria is also regulated by at least one of the proteins (FAT/CD36) that also regulates plasma membrane fatty acid transport. Among individuals, differences in mitochondrial fatty acid oxidation appear to be correlated with the content of mitochondrial CPTI and FAT/CD36. This paper provides a brief overview of mechanisms that regulate LCFA uptake and oxidation in skeletal muscle during exercise and in obesity. We focus largely on our own work on FAT/CD36, which contributes to regulating, in a coordinated fashion, LCFA uptake across the plasma membrane and the mitochondrial membrane. Very little is known about the roles of FATP1-6 on fatty acid transport in skeletal muscle.