P.136DNAJB6 integrates sarcomere protein homeostasis and myogenic signaling in coordinated skeletal muscle stress response

Abstract Background. Long term effects of different doses of ionizing radiation on human skeletal muscle myoblast proliferation, cytokine signalling and stress response capacity were studied in primary cell cultures. Materials and methods. Human skeletal muscle myoblasts obtained from muscle biopsies were cultured and irradiated with a Darpac 2000 X-ray unit at doses of 4, 6 and 8 Gy. Acute effects of radiation were studied by interleukin - 6 (IL-6) release and stress response detected by the heat shock protein (HSP) level, while long term effects were followed by proliferation capacity and cell death. Results. Compared with non-irradiated control and cells treated with inhibitor of cell proliferation Ara C, myoblast proliferation decreased 72 h post-irradiation, this effect was more pronounced with increasing doses. Post-irradiation myoblast survival determined by measurement of released LDH enzyme activity revealed increased activity after exposure to irradiation. The acute response of myoblasts to lower doses of irradiation (4 and 6 Gy) was decreased secretion of constitutive IL-6. Higher doses of irradiation triggered a stress response in myoblasts, determined by increased levels of stress markers (HSPs 27 and 70). Conclusions. Our results show that myoblasts are sensitive to irradiation in terms of their proliferation capacity and capacity to secret IL-6. Since myoblast proliferation and differentiation are a key stage in muscle regeneration, this effect of irradiation needs to be taken in account, particularly in certain clinical conditions.

Download Full-text

Dopamine signaling promotes the xenobiotic stress response and protein homeostasis

The EMBO Journal ◽

10.15252/embj.201592524 ◽

2016 ◽

Vol 35 (17) ◽

pp. 1885-1901 ◽

Cited By ~ 12

Author(s):

Kishore K Joshi ◽

Tarmie L Matlack ◽

Christopher Rongo

Keyword(s):

Stress Response ◽

Protein Homeostasis ◽

Xenobiotic Stress ◽

Dopamine Signaling

Download Full-text

Ankrd2 in Mechanotransduction and Oxidative Stress Response in Skeletal Muscle: New Cues for the Pathogenesis of Muscular Laminopathies

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7318796 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 6

Author(s):

Vittoria Cenni ◽

Snezana Kojic ◽

Cristina Capanni ◽

Georgine Faulkner ◽

Giovanna Lattanzi

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Stress Response ◽

Muscular Dystrophy ◽

Transcriptional Response ◽

Oxidative Stress Response ◽

Ankyrin Repeat ◽

Lamin A ◽

Cellular Reactive Oxygen Species ◽

Cardiac Muscles

Ankrd2 (ankyrin repeats containing domain 2) or Arpp (ankyrin repeat, PEST sequence, and proline-rich region) is a member of the muscle ankyrin repeat protein family. Ankrd2 is mostly expressed in skeletal muscle, where it plays an intriguing role in the transcriptional response to stress induced by mechanical stimulation as well as by cellular reactive oxygen species. Our studies in myoblasts from Emery-Dreifuss muscular dystrophy 2, a LMNA-linked disease affecting skeletal and cardiac muscles, demonstrated that Ankrd2 is a lamin A-binding protein and that mutated lamins found in Emery-Dreifuss muscular dystrophy change the dynamics of Ankrd2 nuclear import, thus affecting oxidative stress response. In this review, besides describing the latest advances related to Ankrd2 studies, including novel discoveries on Ankrd2 isoform-specific functions, we report the main findings on the relationship of Ankrd2 with A-type lamins and discuss known and potential mechanisms involving defective Ankrd2-lamin A interplay in the pathogenesis of muscular laminopathies.

Download Full-text

VITAMIN D PROMOTES PROTEIN HOMEOSTASIS AND LONGEVITY VIA STRESS RESPONSE GENES SKN-1, IRE-1, AND XBP-1

Innovation in Aging ◽

10.1093/geroni/igx004.4445 ◽

2017 ◽

Vol 1 (suppl_1) ◽

pp. 1223-1223

Author(s):

K.J. Dumas ◽

K.A. Mark ◽

D. Bhaumik ◽

S. Davis ◽

R. Brem ◽

...

Keyword(s):

Vitamin D ◽

Stress Response ◽

Protein Homeostasis ◽

Stress Response Genes

Download Full-text

Skeletal Muscle Mass Regulation in Critical Illness

10.1093/med/9780199653461.003.0035 ◽

2014 ◽

Author(s):

Zudin Puthucheary ◽

Hugh Montgomery ◽

Nicholas Hart ◽

Stephen Harridge

Keyword(s):

Skeletal Muscle ◽

Critical Illness ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Bed Rest ◽

Protein Homeostasis ◽

Highly Sensitive ◽

And Function ◽

Inadequate Nutrition

Muscle is a dynamic, plastic, and malleable tissue that is highly sensitive to mechanical and metabolic signals. Muscle mass is regulated by protein homeostasis, with protein being continually turned over, reflecting a balance between synthesis and breakdown. This chapter discusses the effect of critical illness on skeletal muscle mass, protein homeostasis, and the intracellular signalling driving anabolism and catabolism. The focus will be on the unique challenges to which the skeletal muscle are exposed, such as inflammation, sepsis, sedation, and inadequate nutrition, which, in combination with the disuse signals of immobilization and bed rest, engender dramatic changes in muscle structure and function. The mechanisms regulating muscle loss during critical illness are being unravelled, but many questions remain unanswered. Detailed understanding of these mechanisms will help drive strategies to minimize or prevent intensive care-acquired muscle weakness and the long-term consequences experienced by ICU survivors.

Download Full-text

Eccentric Exercise Affects NRF2-mediated Oxidative Stress Response in Skeletal Muscle by Increasing Nuclear NRF2 Content

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000401057.84779.de ◽

2011 ◽

Vol 43 (Suppl 1) ◽

pp. 383 ◽

Cited By ~ 2

Author(s):

Lauren G. MacNeil ◽

Adeel Safdar ◽

Steven K. Baker ◽

Simon Melov ◽

Mark A. Tarnopolsky

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Stress Response ◽

Eccentric Exercise ◽

Oxidative Stress Response

Download Full-text

Comparison of the RpoH-Dependent Regulon and General Stress Response in Neisseria gonorrhoeae

Journal of Bacteriology ◽

10.1128/jb.01807-05 ◽

2006 ◽

Vol 188 (13) ◽

pp. 4769-4776 ◽

Cited By ~ 24

Author(s):

Ishara C. Gunesekere ◽

Charlene M. Kahler ◽

David R. Powell ◽

Lori A. S. Snyder ◽

Nigel J. Saunders ◽

...

Keyword(s):

Stress Response ◽

Heat Shock ◽

Neisseria Gonorrhoeae ◽

Transcriptional Profiling ◽

Transcriptional Response ◽

Protein Homeostasis ◽

Promoter Regions ◽

General Stress Response ◽

Genome Wide ◽

Shock Proteins

ABSTRACT In the gammaproteobacteria the RpoH regulon is often equated with the stress response, as the regulon contains many of the genes that encode what have been termed heat shock proteins that deal with the presence of damaged proteins. However, the betaproteobacteria primarily utilize the HrcA repressor protein to control genes involved in the stress response. We used genome-wide transcriptional profiling to compare the RpoH regulon and stress response of Neisseria gonorrhoeae, a member of the betaproteobacteria. To identify the members of the RpoH regulon, a plasmid-borne copy of the rpoH gene was overexpressed during exponential-phase growth at 37°C. This resulted in increased expression of 12 genes, many of which encode proteins that are involved in the stress response in other species. The putative promoter regions of many of these up-regulated genes contain a consensus RpoH binding site similar to that of Escherichia coli. Thus, it appears that unlike other members of the betaproteobacteria, N. gonorrhoeae utilizes RpoH, and not an HrcA homolog, to regulate the stress response. In N. gonorrhoeae exposed to 42°C for 10 min, we observed a much broader transcriptional response involving 37 differentially expressed genes. Genes that are apparently not part of the RpoH regulon showed increased transcription during heat shock. A total of 13 genes were also down-regulated. From these results we concluded that although RpoH acts as the major regulator of protein homeostasis, N. gonorrhoeae has additional means of responding to temperature stress.

Download Full-text

Multiomics-Identified Intervention to Restore Ethanol-Induced Dysregulated Proteostasis and Secondary Sarcopenia in Alcoholic Liver Disease

Cellular Physiology and Biochemistry ◽

10.33594/000000327 ◽

2021 ◽

Vol 55 (1) ◽

pp. 91-116

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Liver Disease ◽

Mouse Model ◽

Muscle Protein ◽

Protein Homeostasis ◽

Intermediary Metabolites ◽

Intermediary Metabolite ◽

Mtorc1 Signaling ◽

Oxidative Function

BACKGROUND/AIMS: Signaling and metabolic perturbations contribute to dysregulated skeletal muscle protein homeostasis and secondary sarcopenia in response to a number of cellular stressors including ethanol exposure. Using an innovative multiomics-based curating of unbiased data, we identified molecular and metabolic therapeutic targets and experimentally validated restoration of protein homeostasis in an ethanol-fed mouse model of liver disease. METHODS: Studies were performed in ethanol-treated differentiated C2C12 myotubes and physiological relevance established in an ethanol-fed mouse model of alcohol-related liver disease (mALD) or pair-fed control C57BL/6 mice. Transcriptome and proteome from ethanol treated-myotubes and gastrocnemius muscle from mALD and pair-fed mice were analyzed to identify target pathways and molecules. Readouts including signaling responses and autophagy markers by immunoblots, mitochondrial oxidative function and free radical generation, and metabolic studies by gas chromatography-mass spectrometry and sarcopenic phenotype by imaging. RESULTS: Multiomics analyses showed that ethanol impaired skeletal muscle mTORC1 signaling, mitochondrial oxidative pathways, including intermediary metabolite regulatory genes, interleukin-6, and amino acid degradation pathways are β-hydroxymethyl-butyrate targets. Ethanol decreased mTORC1 signaling, increased autophagy flux, impaired mitochondrial oxidative function with decreased tricarboxylic acid cycle intermediary metabolites, ATP synthesis, protein synthesis and myotube diameter that were reversed by HMB. Consistently, skeletal muscle from mALD had decreased mTORC1 signaling, reduced fractional and total muscle protein synthesis rates, increased autophagy markers, lower intermediary metabolite concentrations, and lower muscle mass and fiber diameter that were reversed by β-hydroxymethyl-butyrate treatment. CONCLUSION: An innovative multiomics approach followed by experimental validation showed that β-hydroxymethyl-butyrate restores muscle protein homeostasis in liver disease.

Download Full-text