Idiopathic inflammatory myopathy human derived cells retain their ability to increase mitochondrial function

Idiopathic Inflammatory Myopathies (IIMs) have been studied within the framework of autoimmune diseases where skeletal muscle appears to have a passive role in the illness. However, persiting weakness even after resolving inflammation raises questions about the role that skeletal muscle plays by itself in these diseases. "Non-immune mediated" hypotheses have arisen to consider inner skeletal muscle cell processes as trigger factors in the clinical manifestations of IIMs. Alterations in oxidative phosphorylation, ATP production, calcium handling, autophagy, endoplasmic reticulum stress, among others, have been proposed as alternative cellular pathophysiological mechanisms. In this study, we used skeletal muscle-derived cells, from healthy controls and IIM patients to determine mitochondrial function and mitochondrial ability to adapt to a metabolic stress when deprived of glucose. We hypothesized that mitochondria would be dysfunctional in IIM samples, which was partially true in normal glucose rich growing medium as determined by oxygen consumption rate. However, in the glucose-free and galactose supplemented condition, a medium that forced mitochondria to function, IIM cells increased their respiration, reaching values matching normal derived cells. Unexpectedly, cell death significantly increased in IIM cells under this condition. Our findings show that mitochondria in IIM is functional and the decrease respiration observed is part of an adaptative response to improve survival. The increased metabolic function obtained after forcing IIM cells to rely on mitochondrial synthesized ATP is detrimental to the cell’s viability. Thus, therapeutic interventions that activate mitochondria, could be detrimental in IIM cell physiology, and must be avoided in patients with IIM.

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Skeletal muscle energetics are compromised only during high-intensity contractions in the Goto-Kakizaki rat model of type 2 diabetes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00127.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. R356-R368 ◽

Cited By ~ 3

Author(s):

Matthew T. Lewis ◽

Jonathan D. Kasper ◽

Jason N. Bazil ◽

Jefferson C. Frisbee ◽

Robert W. Wiseman

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Rat Model ◽

Mitochondrial Function ◽

The United States ◽

Gk Rat ◽

Muscle Energetics ◽

Atp Production

Type 2 diabetes (T2D) presents with hyperglycemia and insulin resistance, affecting over 30 million people in the United States alone. Previous work has hypothesized that mitochondria are dysfunctional in T2D and results in both reduced ATP production and glucose disposal. However, a direct link between mitochondrial function and T2D has not been determined. In the current study, the Goto-Kakizaki (GK) rat model of T2D was used to quantify mitochondrial function in vitro and in vivo over a broad range of contraction-induced metabolic workloads. During high-frequency sciatic nerve stimulation, hindlimb muscle contractions at 2- and 4-Hz intensities, the GK rat failed to maintain similar bioenergetic steady states to Wistar control (WC) rats measured by phosphorus magnetic resonance spectroscopy, despite similar force production. Differences were not due to changes in mitochondrial content in red (RG) or white gastrocnemius (WG) muscles (cytochrome c oxidase, RG: 22.2 ± 1.6 vs. 23.3 ± 1.7 U/g wet wt; WG: 10.8 ± 1.1 vs. 12.1 ± 0.9 U/g wet wt; GK vs. WC, respectively). Mitochondria isolated from muscles of GK and WC rats also showed no difference in mitochondrial ATP production capacity in vitro, measured by high-resolution respirometry. At lower intensities (0.25–1 Hz) there were no detectable differences between GK and WC rats in sustained energy balance. There were similar phosphocreatine concentrations during steady-state contraction and postcontractile recovery (τ = 72 ± 6 s GK versus 71 ± 2 s WC). Taken together, these results suggest that deficiencies in skeletal muscle energetics seen at higher intensities are not due to mitochondrial dysfunction in the GK rat.

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Microvascular changes in skeletal muscle in idiopathic inflammatory myopathy

Human Pathology ◽

10.1016/0046-8177(92)90400-w ◽

1992 ◽

Vol 23 (8) ◽

pp. 888-895 ◽

Cited By ~ 34

Author(s):

R. Estruch ◽

J.M. Grau ◽

J. Fernández-Solá ◽

J. Casademont ◽

R. Monforte ◽

...

Keyword(s):

Skeletal Muscle ◽

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Microvascular Changes

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The Functional Roles of RNAs Cargoes Released by Neutrophil-Derived Exosomes in Dermatomyositis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.727901 ◽

2021 ◽

Vol 12 ◽

Author(s):

Liya Li ◽

Xiaoxia Zuo ◽

Di Liu ◽

Hui Luo ◽

Honglin Zhu

Keyword(s):

Skeletal Muscle ◽

Target Genes ◽

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Signalling Pathways ◽

Bioinformatics Analyses ◽

Cutaneous Manifestations ◽

Functional Roles ◽

Real Time Quantitative Pcr ◽

Development And Differentiation

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by cutaneous manifestations. We first identified the profiles of noncoding RNAs (lncRNAs and miRNAs) in peripheral neutrophil exosomes (EXOs) of DM patients and explored their potential functional roles. Bioinformatics analyses were performed with R packages. Real-time quantitative PCR was used to validate the altered RNAs in DM neutrophil EXO-stimulated human dermal microvascular endothelial cells (HDMECs) and human skeletal muscle myoblasts (HSkMCs). In DM neutrophil EXOs, 124 upregulated lncRNAs (with 1,392 target genes), 255 downregulated lncRNAs (with 1867 target genes), 17 upregulated miRNAs (with 2,908 target genes), and 15 downregulated miRNAs (with 2,176 target genes) were identified. GO analysis showed that the differentially expressed (DE) lncRNAs and DE miRNAs participated in interleukin-6 and interferon-beta production, skeletal muscle cell proliferation and development, and endothelial cell development and differentiation. KEGG analysis suggested that DE lncRNAs and DE miRNAs were enriched in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways. Many novel and valuable DE lncRNAs and DE miRNAs interacted and cotargeted in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways. Our study suggests that neutrophil EXOs participate in DM pathogenesis through lncRNAs and miRNAs in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways.

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Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

PLoS ONE ◽

10.1371/journal.pone.0231064 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0231064

Author(s):

Yoshitsugu Oikawa ◽

Rumiko Izumi ◽

Masashi Koide ◽

Yoshihiro Hagiwara ◽

Makoto Kanzaki ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Inclusion Body ◽

Inclusion Body Myositis ◽

Mitochondrial Dynamics ◽

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Mitochondrial Morphology ◽

Atp Production ◽

Bioenergetic Analysis ◽

Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

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OGT regulates mitochondrial biogenesis and function via diabetes susceptibility gene Pdx1

10.2337/figshare.15831735.v1 ◽

2021 ◽

Author(s):

Ramkumar Mohan ◽

Seokwon Jo ◽

Amber Lockridge ◽

Deborah A. Ferrington ◽

Kevin Murray ◽

...

Keyword(s):

Mitochondrial Function ◽

Susceptibility Gene ◽

Mitochondrial Morphology ◽

Cell Physiology ◽

Β Cells ◽

Β Cell ◽

Atp Production ◽

Glcnac Transferase ◽

And Function

O-GlcNAc transferase (OGT), a nutrient-sensor sensitive to glucose flux, is highly expressed in the pancreas. However, the role of OGT in the mitochondria of β-cells is unexplored. Here, we identified the role of OGT in mitochondrial function in β-cells. Constitutive deletion of OGT (βOGTKO) or inducible ablation in mature β-cells (iβOGTKO) causes distinct effects on mitochondrial morphology and function. Islets from βOGTKO, but not iβOGTKO, mice display swollen mitochondria, reduced glucose-stimulated oxygen consumption rate, ATP production and glycolysis. Alleviating ER stress by genetic deletion of Chop did not rescue the mitochondrial dysfunction in βOGTKO mice. We identified altered islet proteome between βOGTKO and iβOGTKO mice. Pancreatic and duodenal homeobox 1 (Pdx1) was reduced in in βOGTKO islets. Pdx1 over-expression increased insulin content and improved mitochondrial morphology and function in βOGTKO islets. These data underscore the essential role of OGT in regulating β-cell mitochondrial morphology and bioenergetics. In conclusion, OGT couples nutrient signal and mitochondrial function to promote normal β-cell physiology. <br>

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Mitochondria-Cytokine Crosstalk Following Skeletal Muscle Injury and Disuse: A Mini-Review

AJP Cell Physiology ◽

10.1152/ajpcell.00462.2020 ◽

2021 ◽

Author(s):

Anita E. Qualls ◽

W. Michael Southern ◽

Jarrod A. Call

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Function ◽

Muscle Injury ◽

Muscle Injuries ◽

Monocyte Chemoattractant Protein 1 ◽

Skeletal Muscle Injury ◽

Atp Production ◽

Bona Fide ◽

Sense And Respond ◽

And Function

Skeletal muscle mitochondria are highly adaptable, highly dynamic organelles that maintain the functional integrity of the muscle fiber by providing ATP for contraction and cellular homeostasis (e.g., Na+/K+ ATPase). Emerging as early modulators of inflammation, mitochondria sense and respond to cellular stress. Mitochondria communicate with the environment, in part, by release of physical signals called mitochondrial-derived damage-associated molecular patterns (mito-DAMPs) and deviation from routine function (e.g. reduced ATP production, Ca2+ overload). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with altered or reduced mitochondrial function can be detrimental to muscle outcomes. Here we describe changes in mitochondrial content, structure, and function following skeletal muscle injury and disuse and highlight the influence of mitochondrial-cytokine crosstalk on muscle regeneration and recovery. While the appropriate therapeutic modulation following muscle stressors remains unknown, retrospective gene expression analysis reveal interleukin-6 (IL-6), interleukin-1b (IL-1b), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1) are significantly upregulated following three unique muscle injuries. These cytokines modulate mitochondrial function and execute bona fide pleiotropic roles that can aid functional recovery of muscle; however, when aberrant, chronically disrupt healing partly by exacerbating mitochondrial dysfunction. Multidisciplinary efforts to delineate the opposing regulatory roles of inflammatory cytokines in the muscle-mitochondrial environment are required to modulate regenerative behavior following skeletal muscle injury or disuse. Future therapeutic directions to consider include quenching or limited release of mito-DAMPs and cytokines present in cytosol or circulation.

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Multiple Skeletal Muscle Metastases from Colon Carcinoma Preceded by Paraneoplastic Dermatomyositis

Case Reports in Medicine ◽

10.1155/2013/392609 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Matteo Landriscina ◽

Assunta Maria Teresa Gerardi ◽

Alberto Fersini ◽

Sergio Modoni ◽

Luca Pio Stoppino ◽

...

Keyword(s):

Skeletal Muscle ◽

Skeletal Muscles ◽

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Skeletal Metastases ◽

Metastatic Colon Cancer ◽

Cutaneous Manifestations ◽

Tumor Metastases ◽

Systemic Symptoms ◽

Skeletal Muscle Metastases

Skeletal muscle metastases are very rare events in colorectal carcinoma. By contrast, dermatomyositis is an idiopathic inflammatory myopathy with characteristic cutaneous manifestations and a well-recognized association with several human malignancies and, among others, colorectal cancer. Here, we report the case of a 71-year-old woman with paraneoplastic dermatomyositis followed by the development of a metastatic colon cancer. Interestingly, this patient developed multiple skeletal metastases which were preceded by the worsening of systemic symptoms of dermatomyositis. This observation suggests that, while muscle tissue is usually resistant to the development of tumor metastases, the inflammatory and immune response which characterizes and boosts paraneoplastic myopathy may represent a favorable soil for tumor cell invasion and metastasization to skeletal muscles.

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Arthritis in Idiopathic Inflammatory Myopathy: Clinical Features and Autoantibody Associations

The Journal of Rheumatology ◽

10.3899/jrheum.131223 ◽

2014 ◽

Vol 41 (6) ◽

pp. 1133-1139 ◽

Cited By ~ 14

Author(s):

Martin Klein ◽

Heřman Mann ◽

Lenka Pleštilová ◽

Zoe Betteridge ◽

Neil McHugh ◽

...

Keyword(s):

Physical Examination ◽

Clinical Features ◽

Strong Association ◽

Inflammatory Myopathy ◽

Clinical Manifestations ◽

Idiopathic Inflammatory Myopathy ◽

Cross Sectional Study ◽

Cross Sectional ◽

History Of ◽

Autoantibody Status

Objective.To determine the prevalence, distribution, and clinical manifestations of arthritis in a cohort of patients with idiopathic inflammatory myopathies (IIM). Associations with autoantibody status and HLA genetic background were also explored.Methods.Consecutive patients with IIM treated in a single center were included in this cross-sectional study (n = 106). History of arthritis, 68-joint and 66-joint tender and swollen joint index, clinical features of IIM, and autoantibody profiles were obtained by clinical examination, personal interview, and review of patient records. High-resolution genotyping in HLA-DRB1 and HLA-DQB1 loci was performed in 71 and 73 patients, respectively.Results.A combination of patients’ medical history and cross-sectional physical examination revealed that arthritis at any time during the disease course had occurred in 56 patients (53%). It was present at the beginning of the disease in 39 patients (37%) including 23 cases (22%) with arthritis preceding the onset of muscle weakness. On physical examination, 29% of patients had at least 1 swollen joint. The most frequently affected areas were wrists, and metacarpophalangeal and proximal interphalangeal joints. Twenty-seven out of the 29 anti-Jo1-positive patients had arthritis at any time during the course of their illness; this prevalence was significantly higher compared to patients without the anti-Jo1 autoantibody (p < 0.0001). No association of arthritis with individual HLA alleles was found.Conclusion.Our data suggest that arthritis is a common feature of myositis. It is frequently present at the onset of disease and it may even precede muscular manifestations of IIM. The most common presentation is a symmetrical, nonerosive polyarthritis affecting particularly the wrists, shoulders, and small joints of the hands. We have confirmed a strong association of arthritis with the presence of the anti-Jo1 antibody.

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The Effect of Branched Chain Amino Acids on Skeletal Muscle Mitochondrial Function in Young and Elderly Adults

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-1822 ◽

2010 ◽

Vol 95 (2) ◽

pp. 894-902 ◽

Cited By ~ 26

Author(s):

Laura L. Tatpati ◽

Brian A. Irving ◽

Andrea Tom ◽

Maureen L. Bigelow ◽

Katherine Klaus ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Mitochondrial Function ◽

Complex I ◽

The Elderly ◽

Branched Chain Amino Acids ◽

Saline Infusion ◽

Elderly Adults ◽

Atp Production ◽

Branched Chain

Abstract Context: A reduction in maximal mitochondrial ATP production rate (MAPR) and mitochondrial DNA (mtDNA) abundance occurs with age in association with muscle weakness and reduced endurance in elderly people. Branched chain amino acids (BCAA) have been extensively used to improve physical performance. Objective: The objective was to determine whether an 8-h infusion of BCAA enhances MAPR equally in healthy young and elderly adults. Methods: Using a crossover study design, we compared the effect BCAA vs. saline infusion in 12 young (23.0 ± 0.8 yr) and 12 elderly (70.7 ± 1.1 yr) participants matched for sex and body mass index. Skeletal muscle MAPR and mtDNA abundance were measured in muscle biopsy samples obtained before and at the end of the 8-h infusion. Results: In young participants, MAPR with the substrates glutamate plus malate (supplying electrons to complex I) and succinate plus rotenone (complex II) increased in response to BCAA infusion, relative to a decline in MAPR in response to the saline infusion. In contrast, MAPR was unaffected by BCAA infusion in the elderly participants. Moreover, mtDNA abundance was lower in the elderly compared with the young participants but was unaffected by the BCAA infusion. Insulin and C-peptide concentrations declined over time during the saline infusion, but these declines were prevented by the BCAA infusion. Conclusions: BCAA increased skeletal muscle MAPR in the young participants in comparison with saline, but this effect was not seen in the elderly participants indicating, that unlike in the young, BCAA does not increase muscle mitochondrial function in the elderly.

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Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00387.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. E38-E43 ◽

Cited By ~ 113

Author(s):

R. Sreekumar ◽

J. Unnikrishnan ◽

A. Fu ◽

J. Nygren ◽

K. R. Short ◽

...

Keyword(s):

Skeletal Muscle ◽

Caloric Restriction ◽

Mitochondrial Function ◽

Citrate Synthase ◽

Control Diet ◽

Radical Scavenging ◽

Reactive Oxygen ◽

Male Rats ◽

Transcript Levels ◽

Atp Production

Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage during aging. Caloric restriction (CR) is reported to reduce oxidative stress and prolong life expectancy in rodents. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle of male rats after feeding them either a control diet or calorie-restricted diet (60% of control diet) for 36 wk to determine the potential mechanism of the beneficial effects of CR. CR enhanced the transcripts of genes involved in reactive oxygen free radical scavenging function, tissue development, and energy metabolism while decreasing expression of those genes involved in signal transduction, stress response, and structural and contractile proteins. Real-time PCR measurments confirmed the changes in transcript levels of cytochrome- c oxidase III, superoxide dismutase (SOD)1, and SOD2 that were noted by the microarray approach. Mitochondrial ATP production and citrate synthase were unaltered by the dietary changes. We conclude that CR alters transcript levels of several genes in skeletal muscle and that mitochondrial function in skeletal muscle remains unaltered by the dietary intervention. Alterations in transcripts of many genes involved in reactive oxygen scavenging function may contribute to the increase in longevity reported with CR.

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