Unravelling the mechanisms regulating muscle mitochondrial biogenesis

2016 ◽  
Vol 473 (15) ◽  
pp. 2295-2314 ◽  
Author(s):  
David A. Hood ◽  
Liam D. Tryon ◽  
Heather N. Carter ◽  
Yuho Kim ◽  
Chris C.W. Chen
Keyword(s):  
Contractile Activity ◽  
Activity Patterns ◽  
Metabolic Health ◽  
Whole Body ◽  
Mitochondrial Content ◽  
Compensatory Response ◽  
Pharmacological Agents ◽  
Regulatory Pathways ◽  
Muscle Disuse ◽  
Biogenesis Of Mitochondria

Skeletal muscle is a tissue with a low mitochondrial content under basal conditions, but it is responsive to acute increases in contractile activity patterns (i.e. exercise) which initiate the signalling of a compensatory response, leading to the biogenesis of mitochondria and improved organelle function. Exercise also promotes the degradation of poorly functioning mitochondria (i.e. mitophagy), thereby accelerating mitochondrial turnover, and preserving a pool of healthy organelles. In contrast, muscle disuse, as well as the aging process, are associated with reduced mitochondrial quality and quantity in muscle. This has strong negative implications for whole-body metabolic health and the preservation of muscle mass. A number of traditional, as well as novel regulatory pathways exist in muscle that control both biogenesis and mitophagy. Interestingly, although the ablation of single regulatory transcription factors within these pathways often leads to a reduction in the basal mitochondrial content of muscle, this can invariably be overcome with exercise, signifying that exercise activates a multitude of pathways which can respond to restore mitochondrial health. This knowledge, along with growing realization that pharmacological agents can also promote mitochondrial health independently of exercise, leads to an optimistic outlook in which the maintenance of mitochondrial and whole-body metabolic health can be achieved by taking advantage of the broad benefits of exercise, along with the potential specificity of drug action.

Effect of hypokinesia-hypodynamia on rat muscle oxidative capacity and glucose uptake

1985 ◽  
Vol 249 (3) ◽  
pp. R308-R312 ◽  
Author(s):  
R. D. Fell ◽  
J. M. Steffen ◽  
X. J. Musacchia
Keyword(s):  
Insulin Sensitivity ◽  
Cytochrome C ◽  
Glucose Uptake ◽  
Citrate Synthase ◽  
Contractile Activity ◽  
Oxidative Capacity ◽  
Whole Body ◽  
Hindlimb Muscles ◽  
Muscle Disuse ◽  
Gastrocnemius Muscles

Whole-body hypokinetic-hypodynamic (H/H) suspension, unlike other models of muscle disuse, allows voluntary contractile activity. This study examined the oxidative capacity and insulin sensitivity of rat hindlimb muscles subjected to 7 days of suspension H/H conditions. Oxidative capacity was determined by measuring citrate synthase activity and cytochrome c concentration in soleus and gastrocnemius muscles. A perfused hindquarter preparation was used to measure glucose uptake rates at rest with physiological and supramaximal concentrations of insulin in the perfusate. Citrate synthase activity was 17% lower in soleus and 23% lower in gastrocnemius muscles from H/H rats. Similarly, a 29% decrease in H/H rat gastrocnemius cytochrome c concentration was observed. Rates of glucose uptake were lower in muscles from H/H rats compared with controls at physiological levels of insulin and did not increase in response to a further increase in insulin concentration. Muscles undergoing a significant loss in mass after 7 days suspension were found to have increased glycogen concentrations. In conclusion, data presented in this study suggest that hindlimb muscle disuse, brought about by whole-body suspension, results in a decreased aerobic capacity in load bearing muscles and a lowered insulin sensitivity in perfused rat hindlimb muscles.

scholarly journals Mitochondrial Bioenergetics and Turnover during Chronic Muscle Disuse

2021 ◽  
Vol 22 (10) ◽  
pp. 5179
Author(s):  
Jonathan M. Memme ◽  
Mikhaela Slavin ◽  
Neushaw Moradi ◽  
David A. Hood
Keyword(s):  
Bed Rest ◽  
Metabolic Health ◽  
Muscle Quality ◽  
Whole Body ◽  
Oxygen Species ◽  
Mitochondrial Quality Control ◽  
Muscle Disuse ◽  
Mitochondrial Alterations ◽  
And Function ◽  
Limb Immobilization

Periods of muscle disuse promote marked mitochondrial alterations that contribute to the impaired metabolic health and degree of atrophy in the muscle. Thus, understanding the molecular underpinnings of muscle mitochondrial decline with prolonged inactivity is of considerable interest. There are translational applications to patients subjected to limb immobilization following injury, illness-induced bed rest, neuropathies, and even microgravity. Studies in these patients, as well as on various pre-clinical rodent models have elucidated the pathways involved in mitochondrial quality control, such as mitochondrial biogenesis, mitophagy, fission and fusion, and the corresponding mitochondrial derangements that underlie the muscle atrophy that ensues from inactivity. Defective organelles display altered respiratory function concurrent with increased accumulation of reactive oxygen species, which exacerbate myofiber atrophy via degradative pathways. The preservation of muscle quality and function is critical for maintaining mobility throughout the lifespan, and for the prevention of inactivity-related diseases. Exercise training is effective in preserving muscle mass by promoting favourable mitochondrial adaptations that offset the mitochondrial dysfunction, which contributes to the declines in muscle and whole-body metabolic health. This highlights the need for further investigation of the mechanisms in which mitochondria contribute to disuse-induced atrophy, as well as the specific molecular targets that can be exploited therapeutically.

Role of p53 in mitochondrial biogenesis and apoptosis in skeletal muscle

2009 ◽  
Vol 37 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Ayesha Saleem ◽  
Peter J. Adhihetty ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Cytochrome C Release ◽  
Mitochondrial Content ◽  
Peroxisome Proliferator Activated Receptor

p53 is a tumor suppressor protein that also plays a role in regulating aerobic metabolism. Since skeletal muscle is a major source of whole body aerobic respiration, it is important to delineate the effects of p53 on muscle metabolism. In p53 knockout (KO) mice, we observed diminished mitochondrial content in mixed muscle and lowered peroxisome proliferator-activated receptor-γ (PPARγ) coactivator (PGC)-1α protein levels in gastrocnemius muscle. In intermyofibrillar (IMF) mitochondria, lack of p53 was associated with reduced respiration and elevated reactive oxygen species production. Permeability transition pore kinetics remained unchanged; however, IMF mitochondrial cytochrome c release was reduced and DNA fragmentation was lowered, illustrating a resistance to mitochondrially driven apoptosis in muscle of KO mice. p53-null animals displayed similar muscle strength but greater fatigability and less locomotory endurance than wild-type (WT) animals. Surprisingly, the adaptive responses in mitochondrial content to running were similar in WT and KO mice. Thus p53 may be important, but not necessary, for exercise-induced mitochondrial biogenesis. In WT animals, acute muscle contractions induced the phosphorylation of p53 in concert with increased activation of upstream kinases AMP-activated protein kinase and p38, indicating a pathway through which p53 may initiate mitochondrial biogenesis in response to contractile activity. These data illustrate a novel role for p53 in maintaining mitochondrial biogenesis, apoptosis, and performance in skeletal muscle.

scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Jean-Marc Wagner ◽  
Bernard Noppen ◽  
Bart Jonckx ◽  
Elke Vermassen ◽  
...  
Keyword(s):  
General Circulation ◽  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Whole Body ◽  
Pharmacological Agents ◽  
Age Related ◽  
Pharmacokinetic Properties ◽  
High Concentrations ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

scholarly journals Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle

2011 ◽  
Vol 300 (4) ◽  
pp. R835-R843 ◽  
Author(s):  
Donato A. Rivas ◽  
Sarah J. Lessard ◽  
Misato Saito ◽  
Anna M. Friedhuber ◽  
Lauren G. Koch ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Aerobic Capacity ◽  
Artificial Selection ◽  
White Muscle ◽  
Metabolic Diseases ◽  
Metabolic Health ◽  
Mitochondrial Content ◽  
Red Muscle ◽  
Selection For

Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30%; P = 0.04), glucose oxidation (∼50%; P = 0.04), and lipid oxidation (∼40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR.

scholarly journals Do Patients with Prostate Cancer Benefit from Exercise Interventions? A Systematic Review and Meta-Analysis

2022 ◽  
Vol 19 (2) ◽  
pp. 972
Author(s):  
Martin Færch Andersen ◽  
Julie Midtgaard ◽  
Eik Dybboe Bjerre
Keyword(s):  
Prostate Cancer ◽  
Aerobic Exercise ◽  
Meta Analysis ◽  
Healthcare Providers ◽  
Cardiovascular Fitness ◽  
Metabolic Health ◽  
Whole Body ◽  
Exercise Interventions ◽  
General Mental Health ◽  
General Physical

Men diagnosed and treated for prostate cancer experience severe adverse effects on quality of life (QoL) and metabolic health, some of which may be preventable or reversible with exercise, the benefits of which healthcare providers and patients increasingly acknowledge, though existing evidence on its effects varies in significance and magnitude. We aimed to review the effect of exercise on QoL and metabolic health in a broad prostate cancer population. A systematic search was conducted in nine databases and eligible trials were included in the meta-analytic procedure. All outcomes were stratified into aerobic exercise, resistance exercise, and a combination of both. The review identified 33 randomised controlled trials (2567 participants) eligible for inclusion. Exercise had a borderline small positive effect on cancer-specific QoL (standardised mean difference (SMD) = 0.10, 95% confidence interval (CI) −0.01–0.22), and a moderate to large effect on cardiovascular fitness (SMD = 0.46, 95% CI 0.34–0.59) with aerobic exercise being the superior modality (SMD = 0.60, 95% CI 0.29–0.90). A positive significant effect was seen in lower body strength, whole-body fat mass, general mental health, and blood pressure. No significant effect was seen in fatigue, lean body mass, and general physical health. We thereby conclude that exercise is effective in improving metabolic health in men diagnosed with prostate cancer, with aerobic exercise as the superior modality. The effect of exercise on QoL was small and not mediated by choice of exercise modality.

Muscular Strengthening Activity Patterns and Metabolic Health Risk Among U.S. Adults:1999-2004 NHANES

2010 ◽  
Vol 42 ◽  
pp. 608
Author(s):  
James R. Churilla ◽  
Peter M. Magyari ◽  
Earl S. Ford ◽  
Eugene C. Fitzhugh
Keyword(s):  
Health Risk ◽  
Activity Patterns ◽  
Metabolic Health

scholarly journals Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling

2018 ◽  
Vol 128 (5) ◽  
pp. 984-991 ◽  
Author(s):  
Chelsea Angel ◽  
Zachary T. Glovak ◽  
Wateen Alami ◽  
Sara Mihalko ◽  
Josh Price ◽  
...  
Keyword(s):  
Body Weight ◽  
Surgical Stress ◽  
Minute Ventilation ◽  
Whole Body ◽  
Compensatory Response ◽  
Leptin Signaling ◽  
Leptin Receptors ◽  
Congenic Lines ◽  
Increased Risk ◽  
Respiratory Variability

Abstract Background Opiate-induced respiratory depression is sexually dimorphic and associated with increased risk among the obese. The mechanisms underlying these associations are unknown. The present study evaluated the two-tailed hypothesis that sex, leptin status, and obesity modulate buprenorphine-induced changes in breathing. Methods Mice (n = 40 male and 40 female) comprising four congenic lines that differ in leptin signaling and body weight were injected with saline and buprenorphine (0.3 mg/kg). Whole-body plethysmography was used to quantify the effects on minute ventilation. The data were evaluated using three-way analysis of variance, regression, and Poincaré analyses. Results Relative to B6 mice with normal leptin, buprenorphine decreased minute ventilation in mice with diet-induced obesity (37.2%; P < 0.0001), ob/ob mice that lack leptin (62.6%; P < 0.0001), and db/db mice with dysfunctional leptin receptors (65.9%; P < 0.0001). Poincaré analyses showed that buprenorphine caused a significant (P < 0.0001) collapse in minute ventilation variability that was greatest in mice with leptin dysfunction. There was no significant effect of sex or body weight on minute ventilation. Conclusions The results support the interpretation that leptin status but not body weight or sex contributed to the buprenorphine-induced decrease in minute ventilation. Poincaré plots illustrate that the buprenorphine-induced decrease in minute ventilation variability was greatest in mice with impaired leptin signaling. This is relevant because normal respiratory variability is essential for martialing a compensatory response to ventilatory challenges imposed by disease, obesity, and surgical stress.

scholarly journals Dietary Fat and Sugar Differentially Affect β-Adrenergic Stimulation of Cardiac ERK and AKT Pathways in C57BL/6 Male Mice Subjected to High-Calorie Feeding

2020 ◽  
Vol 150 (5) ◽  
pp. 1041-1050
Author(s):  
Sadia Ashraf ◽  
Gizem Yilmaz ◽  
Xu Chen ◽  
Romain Harmancey
Keyword(s):  
Signaling Pathways ◽  
Dietary Fat ◽  
Tolerance Test ◽  
Whole Body ◽  
Adrenergic Stimulation ◽  
High Fat ◽  
Cardiac Growth ◽  
Regulatory Pathways ◽  
High Sugar ◽  
Stimulation Of

ABSTRACT Background High dietary fat and sugar promote cardiac hypertrophy independently from an increase in blood pressure. The respective contribution that each macronutrient exerts on cardiac growth signaling pathways remains unclear. Objective The goal of this study was to investigate the mechanisms by which high amounts of dietary fat and sugar affect cardiac growth regulatory pathways. Methods Male C57BL/6 mice (9 wk old; n = 20/group) were fed a standard rodent diet (STD; kcal% protein-fat-carbohydrate, 29-17-54), a high-fat diet (HFD; 20-60-20), a high-fat and high-sugar Western diet (WD; 20-45-35), a high-sugar diet with mixed carbohydrates (HCD; 20-10-70), or a high-sucrose diet (HSD; 20-10-70). Body composition was assessed weekly by EchoMRI. Whole-body glucose utilization was assessed with an intraperitoneal glucose tolerance test. After 6 wk on diets, mice were treated with saline or 20 mg/kg isoproterenol (ISO), and the activity of cardiac growth regulatory pathways was analyzed by immunoblotting. Data were analyzed by ANOVA with data from the STD group included for references only. Results Compared with HCD and HSD, WD and HFD increased body fat mass 2.7- to 3.8-fold (P < 0.001), induced glucose intolerance (P < 0.001), and increased insulin concentrations >1.5-fold (P < 0.05), thereby enhancing basal and ISO-stimulated AKT phosphorylation at both threonine 308 and serine 473 residues (+25−63%; P < 0.05). Compared with HFD, the high-sugar diets potentiated ISO-mediated stimulation of the glucose-sensitive kinases PYK2 (>47%; P < 0.05 for HCD and HSD) and ERK (>34%; P < 0.05 for WD, HCD, and HSD), thereby leading to increased phosphorylation of protein synthesis regulator S6K1 at threonine 389 residue (>64%; P < 0.05 for WD, HCD, and HSD). Conclusions Dietary fat and sugar affect cardiac growth signaling pathways in C57BL/6 mice through distinct and additive mechanisms. The findings may provide new insights into the role of overnutrition in pathological cardiac remodeling.

scholarly journals Associations between Plasma Branched Chain Amino Acids and Health Biomarkers in Response to Resistance Exercise Training Across Age

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3029
Author(s):  
Mariwan H. Sayda ◽  
Bethan E. Phillips ◽  
John P. Williams ◽  
Paul L. Greenhaff ◽  
Daniel J. Wilkinson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Exercise Training ◽  
Resistance Exercise ◽  
Branched Chain Amino Acids ◽  
Metabolic Health ◽  
Whole Body ◽  
Gas Chromatography Mass Spectrometry ◽  
Resistance Exercise Training ◽  
Fasting Plasma ◽  
Branched Chain

Leucine, isoleucine and valine (i.e., the branched chain amino acids, BCAA) play a key role in the support of tissue protein regulation and can be mobilized as energy substrates during times of starvation. However, positive relationships exist between elevated levels of BCAA and insulin resistance (IR). Thus, we sought to investigate the links between fasting plasma BCAA following a progressive resistance exercise training (RET) programme, an intervention known to improve metabolic health. Fasting plasma BCAA were quantified in adults (young: 18–28 y, n = 8; middle-aged: 45–55 y, n = 9; older: 65–75 y, n = 15; BMI: 23–28 kg/m2, both males and females (~50:50), in a cross-sectional, intervention study. Participants underwent 20-weeks whole-body RET. Measurements of body composition, muscle strength (1-RM) and metabolic health biomarkers (e.g., HOMA-IR) were made at baseline and post-RET. BCAA concentrations were determined by gas-chromatography mass spectrometry (GC-MS). No associations were observed across age with BCAA; however, RET elicited (p < 0.05) increases in plasma BCAA (all age-groups), while HOMA-IR scores reduced (p < 0.05) following RET. After RET, positive correlations in lean body mass (p = 0.007) and strength gains (p = 0.001) with fasting BCAA levels were observed. Elevated BCAA are not a robust marker of ageing nor IR in those with a healthy BMI; rather, despite decreasing IR, RET was associated with increased BCAA.

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