A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle

Abstract MuRF1 (TRIM63) is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Overexpression of MuRF1 in adult mice increases ubiquitination of myofibrillar and sarcoplasmic proteins, increases expression of genes associated with neuromuscular junction instability, and causes muscle atrophy. A total of 169 ubiquitination sites on 56 proteins were found to be regulated by MuRF1. MuRF1-mediated ubiquitination targeted both thick and thin filament contractile proteins, as well as, glycolytic enzymes, deubiquitinases, p62, and VCP. These data reveal a potential role for MuRF1 in not only the breakdown of the sarcomere, but also the regulation of metabolism and other proteolytic pathways in skeletal muscle.

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Skeletal muscle myocytes undergo protein loss and reactive oxygen‐mediated NF‐κB activation in response to tumor necrosis factorα

The FASEB Journal ◽

10.1096/fasebj.12.10.971 ◽

1998 ◽

Vol 12 (10) ◽

pp. 871-880

Author(s):

Yi‐Ping Li ◽

Robert J. Schwartz ◽

Ian D. Waddell ◽

Brian R. Holloway ◽

Michael B. Reid

Keyword(s):

Skeletal Muscle ◽

Tumor Necrosis ◽

Reactive Oxygen ◽

Protein Loss

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The relationship between human skeletal muscle pyruvate dehydrogenase phosphatase activity and muscle aerobic capacity

Journal of Applied Physiology ◽

10.1152/japplphysiol.00672.2010 ◽

2011 ◽

Vol 111 (2) ◽

pp. 427-434 ◽

Cited By ~ 8

Author(s):

Lorenzo K. Love ◽

Paul J. LeBlanc ◽

J. Greig Inglis ◽

Nicolette S. Bradley ◽

Jon Choptiany ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Content ◽

Endurance Training ◽

Aerobic Capacity ◽

Pyruvate Dehydrogenase ◽

Human Skeletal Muscle ◽

Citrate Synthase ◽

Tricarboxylic Acid Cycle ◽

Carbohydrate Oxidation ◽

Pyruvate Dehydrogenase Phosphatase

Pyruvate dehydrogenase (PDH) is a mitochondrial enzyme responsible for regulating the conversion of pyruvate to acetyl-CoA for use in the tricarboxylic acid cycle. PDH is regulated through phosphorylation and inactivation by PDH kinase (PDK) and dephosphorylation and activation by PDH phosphatase (PDP). The effect of endurance training on PDK in humans has been investigated; however, to date no study has examined the effect of endurance training on PDP in humans. Therefore, the purpose of this study was to examine differences in PDP activity and PDP1 protein content in human skeletal muscle across a range of muscle aerobic capacities. This association is important as higher PDP activity and protein content will allow for increased activation of PDH, and carbohydrate oxidation. The main findings of this study were that 1) PDP activity ( r2 = 0.399, P = 0.001) and PDP1 protein expression ( r2 = 0.153, P = 0.039) were positively correlated with citrate synthase (CS) activity as a marker for muscle aerobic capacity; 2) E1α ( r2 = 0.310, P = 0.002) and PDK2 protein ( r2 = 0.229, P =0.012) are positively correlated with muscle CS activity; and 3) although it is the most abundant isoform, PDP1 protein content only explained ∼18% of the variance in PDP activity ( r2 = 0.184, P = 0.033). In addition, PDP1 in combination with E1α explained ∼38% of the variance in PDP activity ( r2 = 0.383, P = 0.005), suggesting that there may be alternative regulatory mechanisms of this enzyme other than protein content. These data suggest that with higher muscle aerobic capacity (CS activity) there is a greater capacity for carbohydrate oxidation (E1α), in concert with higher potential for PDH activation (PDP activity).

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Toll-Like Receptors in Ischaemia and Its Potential Role in the Pathophysiology of Muscle Damage in Critical Limb Ischaemia

Cardiology Research and Practice ◽

10.1155/2012/121237 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 19

Author(s):

Hemanshu Patel ◽

Sidney G. Shaw ◽

Xu Shi-Wen ◽

David Abraham ◽

Daryll M. Baker ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Damage ◽

Potential Role ◽

Arterial Disease ◽

Severe Form ◽

Tissue Loss ◽

Critical Limb Ischaemia ◽

Limb Ischaemia ◽

Toll Like Receptors ◽

Skeletal Muscle Damage

Toll-like receptors (TLRs) are key receptors of the innate immune system which are expressed on immune and nonimmune cells. They are activated by both pathogen-associated molecular patterns and endogenous ligands. Activation of TLRs culminates in the release of proinflammatory cytokines, chemokines, and apoptosis. Ischaemia and ischaemia/reperfusion (I/R) injury are associated with significant inflammation and tissue damage. There is emerging evidence to suggest that TLRs are involved in mediating ischaemia-induced damage in several organs. Critical limb ischaemia (CLI) is the most severe form of peripheral arterial disease (PAD) and is associated with skeletal muscle damage and tissue loss; however its pathophysiology is poorly understood. This paper will underline the evidence implicating TLRs in the pathophysiology of cerebral, renal, hepatic, myocardial, and skeletal muscle ischaemia and I/R injury and discuss preliminary data that alludes to the potential role of TLRs in the pathophysiology of skeletal muscle damage in CLI.

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Appendicular lean mass is lower in late compared with early perimenopausal women: potential role of FSH

Journal of Applied Physiology ◽

10.1152/japplphysiol.00315.2019 ◽

2020 ◽

Vol 128 (5) ◽

pp. 1373-1380

Author(s):

Young-Min Park ◽

Catherine M. Jankowski ◽

Cemal Ozemek ◽

Kerry L. Hildreth ◽

Wendy M. Kohrt ◽

...

Keyword(s):

Skeletal Muscle ◽

Lean Mass ◽

Potential Role ◽

Appendicular Lean Mass ◽

Vulnerable Period ◽

Perimenopausal Women

Our data suggest that the late perimenopausal stage may be a vulnerable period for the loss of skeletal muscle, potentially related to elevations in FSH.

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Molecular mechanisms of cardiovascular benefits of exercise: Running for cover from heart disease

Global Cardiology Science and Practice ◽

10.21542/gcsp.2016.3 ◽

2016 ◽

Vol 2016 (1) ◽

Author(s):

Mohamed Hassan ◽

Yasmine Aguib ◽

Magdi Yacoub

Keyword(s):

Skeletal Muscle ◽

Molecular Mechanisms ◽

Potential Role ◽

Peak Exercise ◽

Physically Active ◽

Risk Of Death ◽

Heart Study ◽

Patients With Heart Failure ◽

Ancient Times

The benefits of exercise have been recognized since ancient times. Physically active men and women have an approximately 30% lower risk of death compared with inactive people. Several trials have recently shown the favorable impact of exercise on survival and quality of life. In the PARIS study, four months of endurance exercise training in elderly patients with heart failure and preserved ejection fraction caused a significant improvement in peak exercise capacity. Moreover in the Copenhagen City Heart Study, jogging up to 2.5 h per week at a slow or average pace and a frequency of 3 times per week was associated with a significant increase in survival (6.2 years in men and 5.6 years in women). These findings imply that exercise improves peripheral vascular, microvascular, and/or skeletal muscle functions and causes an increase in oxygen transport and utilization by the active skeletal muscle.1 However, the exact molecular mechanisms of the cardiovascular benefits of exercise remained largely unknown until very recently. Two recent reports serve to shed some light on the potential role for irisin and miRNA-222 in this subject.

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The Potential Role of Insulin-Like Growth Factors in Skeletal Muscle Regeneration

Canadian Journal of Applied Physiology ◽

10.1139/h96-021 ◽

1996 ◽

Vol 21 (4) ◽

pp. 236-250 ◽

Cited By ~ 19

Author(s):

Jamie MacGregor ◽

Wade S. Parkhouse

Keyword(s):

Skeletal Muscle ◽

Growth Hormone ◽

Growth Factors ◽

Muscle Regeneration ◽

Potential Role ◽

Tissue Growth ◽

Skeletal Muscle Regeneration ◽

Tissue Type ◽

Insulin Like Growth Factors

The role of the insulin-like growth factors I and II (IGF-I and IGF-II), previously known as the somatomedins, in general growth and development of various tissues has been known for many years. Thought of exclusively as endocrine factors produced by the liver, and under the control of growth hormone, the somatomedins were known as the intermediaries by which growth hormone exerted its cellular effects during tissue growth and maturation. Eventually it was discovered that virtually every tissue type is capable of autocrine production of the IGFs, and their involvement in skeletal muscle tissue repair and regeneration became apparent. Recent advances in technology have allowed the characterisation of many of the different growth factors believed to play a role in muscle regeneration, and experimental manipulations of cells in culture have provided insight into the effects of the various growth factors on the myoblast. This paper explores the potential role of the IGFs in skeletal muscle regeneration. A critical role of IGF-II in terminal differentiation of proliferating muscle precurser cells following injury is proposed. Key words: growth factors, myogenesis, skeletal muscle regeneration

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Abstract 14297: Potential Role of the Tumor Suppressor WWOX in Mediating Skeletal Muscle-Lung Vasculature Crosstalk in PH-HFpEF

Circulation ◽

10.1161/circ.142.suppl_3.14297 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Gunner Halliday ◽

Yang Bai ◽

Marta T Gomes ◽

Dmitry Goncharov ◽

Elena Goncharova ◽

...

Keyword(s):

Skeletal Muscle ◽

Tumor Suppressor ◽

Potential Role ◽

Pulmonary Vascular Remodeling ◽

Expression Levels ◽

Promote Cell Proliferation ◽

Pulmonary Arterial ◽

Arterial Smooth Muscle Cells ◽

Group 2

Introduction: Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), particularly in the context of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide. At present, no specific effective therapy has been identified mainly due to the fact that major pathways involved in the regulation of PH-HFpEF are still not well understood. Results: We have recently reported on a role of skeletal muscle sirtuin-3 (SIRT3) in modulating PH-HFpEF. Using skeletal muscle-specific SIRT3 knockout mice ( Sirt3 skm-/- ), we showed that absence of SIRT3 in skeletal muscle drastically reduced the pulmonary vascular tree accompanied by vascular proliferative remodeling. Interestingly, we found that expression levels of the tumor suppressor WW domain-containing oxidoreductase (WWOX) were decreased in pulmonary arterial smooth muscle cells (PASMCs) obtained from Sirt3 skm-/- mice, while no changes in SIRT3 activation levels were detected. Reduced WWOX expression levels were also found in PASMCs isolated from SU5416/Obese ZSF1 (Ob-Su) rat model of PH-HFpEF, in which the levels of SIRT3 activation were found to be decreased in skeletal muscle, but not in the lungs and PASMCs. No changes of WWOX levels were observed in skeletal muscle of Ob-Su rats or in pulmonary artery endothelial cells (PAECs) treated with plasma obtained from Ob-Su rats. Conclusions: Since reduction of WWOX in PASMCs has been shown to promote cell proliferation, HIF1α stabilization and pulmonary arterial hypertension (PAH; Group 1), our data suggest a potential role of WWOX in mediating skeletal muscle SIRT3 deficiency-associated remote pulmonary vascular remodeling in PH-HFpEF.

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