Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease

2015 ◽  
Vol 129 (7) ◽  
pp. 589-599 ◽  
Author(s):  
Joaquin Perez-Schindler ◽  
Andrew Philp
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Nuclear Receptors ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Muscle Metabolism ◽  
Cellular Level ◽  
Expression Of Genes

Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome; however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease.

Abstract P463: Objectively Measured Moderate-to-Vigorous Physical Activity is Associated With Decreased Myosteatosis in African Caribbean Adults

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Iva Miljkovic ◽  
Allison Kuipers ◽  
Ryan Cvejkus ◽  
Victor Wheeler ◽  
Joseph Zmuda
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Sedentary Behavior ◽  
Metabolic Diseases ◽  
Vigorous Physical Activity ◽  
Middle Aged ◽  
Fat Infiltration ◽  
Muscle Attenuation ◽  
Muscle Fat Infiltration ◽  
Objectively Measured

Increased skeletal muscle fat infiltration (i.e. myosteatosis) is now recognized as a major risk factor for cardio-metabolic diseases. Therefore, a lifestyle modification that reduces myosteatosis would be of great public health importance. However, studies examining the association of relevant lifestyle factors with this ectopic fat depot are lacking, particularly in African ancestry populations who have a very high burden of cardio-metabolic diseases. The aim of this study was to examine the relation between objectively measured physical activity and sedentary behavior with computed tomography measured calf muscle attenuation among middle-aged and elderly African-Caribbeans from the population-based Tobago Health Study. Preliminary analyses were conducted among 134 women (mean age 59 yrs, mean BMI 31.6 kg/m 2 ) and 355 men (mean age 62 yrs, mean BMI 28 kg/m 2 ). Physical activity was measured using the SenseWear Pro armband worn for 4-7 days. We calculated the mean duration of waking time engaged in light physical activity (LPA), moderate to vigorous activity (MVPA), and sedentary behavior (SB) per day. Skeletal muscle attenuation (mg/cm 3 ) reflects the fat content of the muscle such that greater skeletal muscle fat infiltration is reflected by lower attenuation. Women spent less time in LPA (146 vs. 270 min/day) and MVPA (15 vs. 41 min/day), but more time in SB (789 vs. 647 min/day) than men (all p<0.0001) after adjustments for gender differences in age. Muscle attenuation was lower among women compared with men (70.5 vs. 72.7 mg/cm3; age and BMI adjusted p<0.0001). In both women and men, muscle attenuation was positively correlated with the LPA and MVPA, and inversely with time spent in SB (spearman correlation coefficients (r) ranged from 0.21 to 0.39, all p<0.006 adjusted for age). Upon additional adjustment for BMI, in both women and men, the association of muscle attenuation with MVPA remained significant (r=0.21 and r=0.18, respectively, both p<0.03), but there was no association with LPA. Percent time spent in SB was associated with muscle attenuation only among women after additional adjustment for BMI (women: -0.16, p=0.052), and we also found a significant sex interaction effect of SB on muscle attenuation (p=0.035). Our preliminary findings suggest that there is significant association between MVPA and myosteatosis among middle-aged and elderly African Caribbeans. However, SB may only be relevant for myosteatosis among women. Future analyses will be conducted in a larger sample from this cohort to confirm our findings and to test for independence from other potential confounding factors, such as diet, sleep patterns, adiposity distribution, and diabetes.

scholarly journals Exercise-Induced Myokines can Explain the Importance of Physical Activity in the Elderly: An Overview

Healthcare ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 378
Author(s):  
Jenny Hyosun Kwon ◽  
Kyoung Min Moon ◽  
Kyueng-Whan Min
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Metabolic Diseases ◽  
The Elderly ◽  
Anaerobic Exercise ◽  
Small Proteins ◽  
Stromal Cell Derived Factor ◽  
Exercise Induced ◽  
Aerobic And Anaerobic

Physical activity has been found to aid the maintenance of health in the elderly. Exercise-induced skeletal muscle contractions lead to the production and secretion of many small proteins and proteoglycan peptides called myokines. Thus, studies on myokines are necessary for ensuring the maintenance of skeletal muscle health in the elderly. This review summarizes 13 myokines regulated by physical activity that are affected by aging and aims to understand their potential roles in metabolic diseases. We categorized myokines into two groups based on regulation by aerobic and anaerobic exercise. With aging, the secretion of apelin, β-aminoisobutyric acid (BAIBA), bone morphogenetic protein 7 (BMP-7), decorin, insulin-like growth factor 1 (IGF-1), interleukin-15 (IL-15), irisin, stromal cell-derived factor 1 (SDF-1), sestrin, secreted protein acidic rich in cysteine (SPARC), and vascular endothelial growth factor A (VEGF-A) decreased, while that of IL-6 and myostatin increased. Aerobic exercise upregulates apelin, BAIBA, IL-15, IL-6, irisin, SDF-1, sestrin, SPARC, and VEGF-A expression, while anaerobic exercise upregulates BMP-7, decorin, IGF-1, IL-15, IL-6, irisin, and VEGF-A expression. Myostatin is downregulated by both aerobic and anaerobic exercise. This review provides a rationale for developing exercise programs or interventions that maintain a balance between aerobic and anaerobic exercise in the elderly.

scholarly journals Physical Activity Is the Key Determinant of Skeletal Muscle Mitochondrial Function in Type 2 Diabetes

2012 ◽  
Vol 97 (9) ◽  
pp. 3261-3269 ◽  
Author(s):  
F. H. J. van Tienen ◽  
S. F. E. Praet ◽  
H. M. de Feyter ◽  
N. M. van den Broek ◽  
P. J. Lindsey ◽  
...  
Keyword(s):  
Physical Activity ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Mitochondrial Function

The microRNA miR-696 regulates PGC-1α in mouse skeletal muscle in response to physical activity

2010 ◽  
Vol 298 (4) ◽  
pp. E799-E806 ◽  
Author(s):  
Wataru Aoi ◽  
Yuji Naito ◽  
Katsura Mizushima ◽  
Yoshikazu Takanami ◽  
Yukari Kawai ◽  
...  
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Stress Responses ◽  
Translational Regulation ◽  
Muscle Metabolism ◽  
Exercise Group ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Nutrient Metabolism ◽  
Peroxisome Proliferator Activated Receptor

MicroRNAs (miRNAs) are small noncoding RNAs involved in posttranscriptional gene regulation that have been shown to be involved in growth, development, function, and stress responses of various organs. The purpose of this study was to identify the miRNA response to physical activity, which was related to functions such as nutrient metabolism, although the miRNAs involved are currently unknown. C57BL/6 mice were divided into exercise and control groups. The exercise group performed running exercise, with a gradual increase of the load over 4 wk. On the other hand, to examine the effect of muscle inactivity, the unilateral hindlimbs of other mice were fixed in a cast for 5 days. Microarray analysis for miRNA in gastrocnemius revealed that miR-696 was markedly affected by both exercise and immobilization, showing opposite responses to these two interventions. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which was increased by exercise and decreased by immobilization in the protein level, was predicted as a target regulated by miR-696. In cultured myocytes, intracellular miR-696 variation led to negative regulation of PGC-1α protein along with the expression of mRNAs for downstream genes. In addition, we found decreases in the biogenesis of mitochondria and fatty acid oxidation in miR-696-overexpressing myocytes compared with normal control myocytes. These observations demonstrate that miR-696 is a physical activity-dependent miRNA involved in the translational regulation of PGC-1α and skeletal muscle metabolism in mice.

scholarly journals PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity

2010 ◽  
Vol 299 (2) ◽  
pp. E145-E161 ◽  
Author(s):  
Vitor A. Lira ◽  
Carley R. Benton ◽  
Zhen Yan ◽  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Mitochondrial Biogenesis ◽  
Therapeutic Potential ◽  
Fiber Type ◽  
Acid Oxidation ◽  
Physiological Limits ◽  
Exercise Induced

The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α (PGC-1α) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of 1) the role of PGC-1α in exercise-mediated muscle adaptation and 2) the possible insulin-sensitizing role of PGC-1α. To these ends, the following questions are addressed. 1) How is PGC-1α regulated, 2) what adaptations are indeed dependent on PGC-1α action, 3) is PGC-1α altered in insulin resistance, and 4) are PGC-1α-knockout and -transgenic mice suitable models for examining therapeutic potential of this coactivator? In skeletal muscle, an orchestrated signaling network, including Ca2+-dependent pathways, reactive oxygen species (ROS), nitric oxide (NO), AMP-dependent protein kinase (AMPK), and p38 MAPK, is involved in the control of contractile protein expression, angiogenesis, mitochondrial biogenesis, and other adaptations. However, the p38γ MAPK/PGC-1α regulatory axis has been confirmed to be required for exercise-induced angiogenesis and mitochondrial biogenesis but not for fiber type transformation. With respect to a potential insulin-sensitizing role of PGC-1α, human studies on type 2 diabetes suggest that PGC-1α and its target genes are only modestly downregulated (≤34%). However, studies in PGC-1α-knockout or PGC-1α-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1α does not have an insulin-sensitizing role. In contrast, a modest (∼25%) upregulation of PGC-1α, within physiological limits, does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38γ MAPK-PGC-1α regulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1α, within physiological limits, have revealed its insulin-sensitizing effects.

scholarly journals Mitochondrial Function, Skeletal Muscle Metabolism, and Iron Deficiency in Heart Failure

Circulation ◽  
2019 ◽  
Vol 139 (21) ◽  
pp. 2399-2402 ◽  
Author(s):  
Peter van der Meer ◽  
Haye H. van der Wal ◽  
Vojtech Melenovsky
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Iron Deficiency ◽  
Mitochondrial Function ◽  
Muscle Metabolism ◽  
Skeletal Muscle Metabolism

scholarly journals The role of calcium and calcium/calmodulin-dependent kinases in skeletal muscle plasticity and mitochondrial biogenesis

2004 ◽  
Vol 63 (2) ◽  
pp. 279-286 ◽  
Author(s):  
Eva R. Chin
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Activated T Cells ◽  
Muscle Plasticity ◽  
Hypertrophic Growth ◽  
Muscle Gene Expression ◽  
Calcium Calmodulin Dependent ◽  
Biological Phenomena ◽  
Expression Of Genes ◽  
Muscle Gene

Intracellular Ca2+plays an important role in skeletal muscle excitation–contraction coupling and also in excitation–transcription coupling. Activity-dependent alterations in muscle gene expression as a result of increased load (i.e. resistance or endurance training) or decreased activity (i.e. immobilization or injury) are tightly linked to the level of muscle excitation. Differential expression of genes in slow- and fast-twitch fibres is also dependent on fibre activation. Both these biological phenomena are, therefore, tightly linked to the amplitude and duration of the Ca2+transient, a signal decoded downstream by Ca2+-dependent transcriptional pathways. Evidence is mounting that the calcineurin–nuclear factor of activated T-cells pathway and the Ca2+/calmodulin-dependent kinases (CaMK) II and IV play important roles in regulating oxidative enzyme expression, mitochondrial biogenesis and expression of fibre-type specific myofibrillar proteins. CaMKII is known to decode frequency-dependent information and is activated during hypertrophic growth and endurance adaptations. Thus, it was hypothesized that CaMKII, and possibly CaMKIV, are down regulated during muscle atrophy and levels of expression of CaMKIIα, -IIβ, -IIγ and -IV were assessed in skeletal muscles from young, aged and denervated rats. The results indicate that CaMKIIγ, but not CaMKIIα or -β, is up regulated in aged and denervated soleus muscle and that CaMKIV is absent in skeletal but not cardiac muscle. Whether CaMKIIγ up-regulation is part of the pathology of wasting or a result of some adaptational response to atrophy is not known. Future studies will be important in determining whether insights from the adaptational response of muscle to increased loads will provide pharmacological approaches for increasing muscle strength or endurance to counter muscle wasting.

scholarly journals Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle

2014 ◽  
Vol 221 (3) ◽  
pp. 391-403 ◽  
Author(s):  
Gabriela Capllonch-Amer ◽  
Miquel Sbert-Roig ◽  
Bel M Galmés-Pascual ◽  
Ana M Proenza ◽  
Isabel Lladó ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sexual Dimorphism ◽  
Sex Hormones ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Female Rats ◽  
Metabolic Effects ◽  
Cultured Myotubes

Sexual dimorphism has been found in mitochondrial features of skeletal muscle, with female rats showing greater mitochondrial mass and function compared with males. Adiponectin is an insulin-sensitizing adipokine whose expression has been related to mitochondrial function and that is also expressed in skeletal muscle, where it exerts local metabolic effects. The aim of this research was to elucidate the role of sex hormones in modulation of mitochondrial function, as well as its relationship with adiponectin production in rat skeletal muscle. Anin vivostudy with ovariectomized Wistar rats receiving or not receiving 17β-estradiol (E2) (10 μg/kg per 48 h for 4 weeks) was carried out, in parallel with an assay of cultured myotubes (L6E9) treated with E2(10 nM), progesterone (Pg; 1 μM), or testosterone (1 μM). E2upregulated the markers of mitochondrial biogenesis and dynamics, and also of mitochondrial function in skeletal muscle and L6E9. Althoughin vivoE2supplementation only partially restored the decreased adiponectin expression levels induced by ovariectomy, these were enhanced by E2and Pg treatment in cultured myotubes, whereas testosterone showed no effects. Adiponectin receptor 1 expression was increased by E2treatment, bothin vivoandin vitro, but testosterone decreased it. In conclusion, our results are in agreement with the sexual dimorphism previously reported in skeletal muscle mitochondrial function and indicate E2to be its main effector, as it enhances mitochondrial function and diminishes oxidative stress. Moreover, our data support the idea of the existence of a link between mitochondrial function and adiponectin expression in skeletal muscle, which could be modulated by sex hormones.

T3 increases lactate transport and the expression of MCT4, but not MCT1, in rat skeletal muscle

2003 ◽  
Vol 285 (3) ◽  
pp. E622-E628 ◽  
Author(s):  
Yuxiang Wang ◽  
Mio Tonouchi ◽  
Dragana Miskovic ◽  
Hideo Hatta ◽  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Gastrocnemius Muscle ◽  
Muscle Metabolism ◽  
Monocarboxylate Transporters ◽  
Rat Skeletal Muscle ◽  
Lactate Transport ◽  
Expression Of Genes ◽  
Sarcolemmal Vesicles ◽  
White Gastrocnemius

Triiodothyronine (T3) regulates the expression of genes involved in muscle metabolism. Therefore, we examined the effects of a 7-day T3 treatment on the monocarboxylate transporters (MCT)1 and MCT4 in heart and in red (RG) and white gastrocnemius muscle (WG). We also examined rates of lactate transport into giant sarcolemmal vesicles and the plasmalemmal MCT1 and MCT4 in these vesicles. Ingestion of T3 markedly increased circulating serum T3 ( P < 0.05) and reduced weight gain ( P < 0.05). T3 upregulated MCT1 mRNA (RG +77, WG +49, heart +114%, P < 0.05) and MCT4 mRNA (RG +300, WG +40%). However, only MCT4 protein expression was increased (RG +43, WG +49%), not MCT1 protein expression. No changes in MCT1 protein were observed in any tissue. T3 treatment doubled the rate of lactate transport when vesicles were exposed to 1 mM lactate ( P < 0.05). However, plasmalemmal MCT4 was only modestly increased (+13%, P < 0.05). We conclude that T3 1) regulates MCT4, but not MCT1, protein expression and 2) increases lactate transport rates. This latter effect is difficult to explain by the modest changes in plasmalemmal MCT4. We speculate that either the activity of sarcolemmal MCTs has been altered or else other MCTs in muscle may have been upregulated.

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