Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia

Objective: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. Methods: The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. Results: Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. Conclusions: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted.

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The Physiology of Heat Stress: A Shift in Metabolic Priorities at the Systemic and Cellular Levels

Ceiba ◽

10.5377/ceiba.v54i1.2778 ◽

2016 ◽

Vol 54 (1) ◽

pp. 50-58

Author(s):

Robert P. Rhoads ◽

Lance H. Baumgard ◽

Lidan Zhao

Keyword(s):

Skeletal Muscle ◽

Heat Stress ◽

Feed Intake ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Well Being ◽

Production Performance ◽

Whole Body ◽

Energy Status ◽

Whole Body Metabolism

At the onset of heat stress, cattle initiate a series of whole body adaptations in an effort to cope with and dissipate additional heat load. These include well-known physiological changes such as increased respiration rate and sweating rate and decreased feed intake. Environmentally induced hyperthermia in ruminants depresses production as a consequence of reduced feed intake but it is unclear how shifts in metabolism may further affect production performance and physiological acclimation. Our evidence indicates that cattle experiencing heat stress do not appear to engage metabolic and glucose-sparing adaptations consistent with their plane of nutrition. In this context, the liver is uniquely positioned to direct exogenously and endogenously derived nutrients for use by other metabolically active tissues such as the mammary gland and skeletal muscle. Despite the prominent role of the liver in whole-body metabolism, alterations in the molecular mechanisms leading to hepatic adaptation during heat challenge are unclear. We are using management tools and metabolic modifiers, such as bovine somatotropin, in an attempt to better understand and improve hepatic function during heat stress. Because a large proportion of an animal’s mass is comprised of skeletal muscle, alterations in skeletal muscle metabolism and function can have a profound impact on whole-animal energy metabolism and nutrient homeostasis especially during periods of stress. We have initiated studies to understand how hyperthermia influences the set points of several metabolic pathways within skeletal muscle. It appears that during heat stress bovine skeletal muscle experiences mitochondrial dysfunction leading to impaired cellular energy status. Finally, investigations into adipose tissue metabolism demonstrate impaired lipolytic functions likely due to a refractory nature to adrenergic stimuli. Taken together, this may have broad implications for the reduced production and heat intolerance seen during heat stress especially if tissue(s) are not able to make necessary contributions to whole-body energy homeostasis. Accurately understanding the biological mechanism(s) by which thermal stress reduces animal performance is critical for developing novel approaches (i.e. genetic, managerial and nutritional) to preserve growth and lactation especially given the critical importance of nutrients, such as glucose, to animal production and well being in these situations.

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Regulation of skeletal muscle energy/nutrient-sensing pathways during metabolic adaptation to fasting in healthy humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00215.2014 ◽

2014 ◽

Vol 307 (10) ◽

pp. E885-E895 ◽

Cited By ~ 17

Author(s):

Marjolein A. Wijngaarden ◽

Leontine E. H. Bakker ◽

Gerard C. van der Zon ◽

Peter A. C. 't Hoen ◽

Ko Willems van Dijk ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Lipid Oxidation ◽

Energy Homeostasis ◽

Nutrient Sensing ◽

Whole Body ◽

Metabolic Adaptation ◽

Protein Kinase Activity ◽

Short Term ◽

Muscle Energy

During fasting, rapid metabolic adaptations are required to maintain energy homeostasis. This occurs by a coordinated regulation of energy/nutrient-sensing pathways leading to transcriptional activation and repression of specific sets of genes. The aim of the study was to investigate how short-term fasting affects whole body energy homeostasis and skeletal muscle energy/nutrient-sensing pathways and transcriptome in humans. For this purpose, 12 young healthy men were studied during a 24-h fast. Whole body glucose/lipid oxidation rates were determined by indirect calorimetry, and blood and skeletal muscle biopsies were collected and analyzed at baseline and after 10 and 24 h of fasting. As expected, fasting induced a time-dependent decrease in plasma insulin and leptin levels, whereas levels of ketone bodies and free fatty acids increased. This was associated with a metabolic shift from glucose toward lipid oxidation. At the molecular level, activation of the protein kinase B (PKB/Akt) and mammalian target of rapamycin pathways was time-dependently reduced in skeletal muscle during fasting, whereas the AMP-activated protein kinase activity remained unaffected. Furthermore, we report some changes in the phosphorylation and/or content of forkhead protein 1, sirtuin 1, and class IIa histone deacetylase 4, suggesting that these pathways might be involved in the transcriptional adaptation to fasting. Finally, transcriptome profiling identified genes that were significantly regulated by fasting in skeletal muscle at both early and late time points. Collectively, our study provides a comprehensive map of the main energy/nutrient-sensing pathways and transcriptomic changes during short-term adaptation to fasting in human skeletal muscle.

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Exercise and MEF2–HDAC interactions

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-082 ◽

2007 ◽

Vol 32 (5) ◽

pp. 852-856 ◽

Cited By ~ 21

Author(s):

Sean L. McGee

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Nuclear Export ◽

Energy Homeostasis ◽

Whole Body ◽

Positive Health ◽

Exercise Induced ◽

Amp Activated Protein Kinase ◽

Body Energy ◽

Skeletal Muscle Adaptations

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

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Metabolic adaptations in skeletal muscle, adipose tissue, and whole-body oxidative capacity in response to resistance training

European Journal of Applied Physiology ◽

10.1007/s00421-014-2879-9 ◽

2014 ◽

Vol 114 (7) ◽

pp. 1463-1471 ◽

Cited By ~ 24

Author(s):

Malin Alvehus ◽

Niklas Boman ◽

Karin Söderlund ◽

Michael B. Svensson ◽

Jonas Burén

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Resistance Training ◽

Oxidative Capacity ◽

Whole Body ◽

Metabolic Adaptations

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Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

10.2337/figshare.13652960 ◽

2021 ◽

Author(s):

Ada Admin ◽

David M Presby ◽

Michael C Rudolph ◽

Vanessa D Sherk ◽

Matthew R Jackman ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Energy Expenditure ◽

Lipoprotein Lipase ◽

Weight Regain ◽

Energy Homeostasis ◽

Fat Metabolism ◽

Fat Oxidation ◽

Oxidative Capacity ◽

Expression Of Genes

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism genes were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.

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The vitamin D receptor regulates mitochondrial function in C2C12 myoblasts

AJP Cell Physiology ◽

10.1152/ajpcell.00568.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. C536-C541 ◽

Cited By ~ 6

Author(s):

Stephen P. Ashcroft ◽

Joseph J. Bass ◽

Abid A. Kazi ◽

Philip J. Atherton ◽

Andrew Philp

Keyword(s):

Skeletal Muscle ◽

Vitamin D ◽

Protein Content ◽

Vitamin D Receptor ◽

Mitochondrial Function ◽

Mitochondrial Respiration ◽

Oxidative Capacity ◽

C2c12 Myoblasts

Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity; however, the mechanistic bases of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH)2D3 to the regulation of skeletal muscle mitochondrial function in vitro; however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we used lentivirus-mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared with an shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes ( P < 0.001). VDR-KD myoblasts displayed a 30%, 30%, and 36% reduction in basal, coupled, and maximal respiration, respectively ( P < 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33%, and 48% reduction in basal, coupled, and maximal respiration ( P < 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATPOx) was reduced by 20%, suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content, as well as markers of mitochondrial fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.

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Irradiation impairs mitochondrial function and skeletal muscle oxidative capacity: significance for metabolic complications in cancer survivors

Metabolism ◽

10.1016/j.metabol.2019.154025 ◽

2020 ◽

Vol 103 ◽

pp. 154025 ◽

Cited By ~ 1

Author(s):

Nadia M.L. Amorim ◽

Anthony Kee ◽

Adelle C.F. Coster ◽

Christine Lucas ◽

Sarah Bould ◽

...

Keyword(s):

Skeletal Muscle ◽

Cancer Survivors ◽

Mitochondrial Function ◽

Oxidative Capacity ◽

Metabolic Complications ◽

Muscle Oxidative Capacity

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Role of the motor nerve in activity-induced enzymatic adaptation in skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.1982.242.5.c272 ◽

1982 ◽

Vol 242 (5) ◽

pp. C272-C277 ◽

Cited By ~ 83

Author(s):

J. Henriksson ◽

H. Galbo ◽

E. Blomstrand

Keyword(s):

Skeletal Muscle ◽

Gastrocnemius Muscle ◽

Tricarboxylic Acid Cycle ◽

Motor Nerve ◽

Oxidative Capacity ◽

Control Group ◽

Marker Enzyme ◽

Muscle Weight ◽

Enzymatic Adaptation ◽

Gastrocnemius Muscles

The sciatic nerve was cut on one side in 11 male cats, and a piece of the nerve was removed. The cats were then divided at random into two groups, a stimulation group (S) of five cats and a control group (C) of six cats. Bilateral electrical stimulation (2 Hz) of the gastrocnemius muscle (directly or via the motor nerve) was carried out in the S cats 4 h/day, 3 days/wk for 4 wk. The voltage delivered was adjusted in each cat so that both gastrocnemius muscles lifted identical loads the same distance. The activity of the tricarboxylic acid cycle marker enzyme succinate dehydrogenase (SDH) per unit of muscle weight more than doubled in response to stimulation both in the intact and the denervated gastrocnemius muscle. Stimulation did not affect the activity of the glycolytic marker enzyme 6-phosphofructokinase (PFK) or muscle capillarization. Denervation resulted in pronounced (approx 50%) fiber atrophy, which was not prevented by the stimulation. It is concluded that the presence of the motor nerve per se is not necessary for an activity-induced adaptation of the oxidative capacity of skeletal muscle.

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Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle

PPAR Research ◽

10.1155/2008/172676 ◽

2008 ◽

Vol 2008 ◽

pp. 1-7 ◽

Cited By ~ 23

Author(s):

Pieter de Lange ◽

Assunta Lombardi ◽

Elena Silvestri ◽

Fernando Goglia ◽

Antonia Lanni ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Oxidative Capacity ◽

Whole Body ◽

Lipid Homeostasis ◽

Peroxisome Proliferator ◽

Transcriptional Program ◽

Peroxisome Proliferator Activated Receptor ◽

Peroxisome Proliferator Activated Receptors ◽

Metabolic Action

The peroxisome proliferator-activated receptors (PPARs), which are ligand-inducible transcription factors expressed in a variety of tissues, have been shown to perform key roles in lipid homeostasis. In physiological situations such as fasting and physical exercise, one PPAR subtype, PPARδ, triggers a transcriptional program in skeletal muscle leading to a switch in fuel usage from glucose/fatty acids to solely fatty acids, thereby drastically increasing its oxidative capacity. The metabolic action of PPARδ has also been verified in humans. In addition, it has become clear that the action of PPARδ is not restricted to skeletal muscle. Indeed, PPARδ has been shown to play a crucial role in whole-body lipid homeostasis as well as in insulin sensitivity, and it is active not only in skeletal muscle (as an activator of fat burning) but also in the liver (where it can activate glycolysis/lipogenesis, with the produced fat being oxidized in muscle) and in the adipose tissue (by incrementing lipolysis). The main aim of this review is to highlight the central role for activated PPARδ in the reversal of any tendency toward the development of insulin resistance.

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