The Effect of Mutation of L345P in the Desmin Gene on the Process of Autophagy in Muscle Cells of the C2C12 Line

Сухарева, К. С.; Smolina, Natalia; Knyazeva, Anastasia; Kalugina, K. K.; Khudyakov, A. A.; Kostareva, Anna

doi:10.1134/s1990519x21010119

Cited by 2 publications

(3 citation statements)

References 24 publications

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“…According to our the previous study for further experiments, we chose the earliest time point of 2 h post-stimulation as the most informative to assess the autophagy dynamics in C2C12 cells transduced with Des mutations (Sukhareva et al 2021 ). We considered later time points less informative due to the less striking difference between WT and mutant cells.…”

Section: Resultsmentioning

confidence: 99%

“…In the our studies, we described a regular turnover of LC3-I to LC3-II in NTC and Des WT C2C12 cells during autophagy induction to characterize the autophagy flux in muscle cells (Sukhareva et al 2021 ). The level of LC3-I steadily declined with the time of nutritional stress, while the level of LC3-II did not change or only slightly increased at the beginning and then substantially degraded to the later time points.…”

Section: Discussionmentioning

confidence: 99%

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Desmin mutations impact the autophagy flux in C2C12 cell in mutation-specific manner

Sukhareva,

Smolina,

Churkina

et al. 2023

Cell Tissue Res

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Desmin is the main intermediate filament of striated and smooth muscle cells and plays a crucial role in maintaining the stability of muscle fiber during contraction and relaxation cycles. Being a component of Z-disk area, desmin integrates autophagic pathways, and the disturbance of Z-disk proteins’ structure negatively affects chaperone-assisted selective autophagy (CASA). In the present study, we focused on alteration of autophagy flux in myoblasts expressing various Des mutations. We applied Western blotting, immunocytochemistry, RNA sequencing, and shRNA approach to demonstrate that DesS12F, DesA357P, DesL345P, DesL370P, and DesD399Y mutations. Mutation-specific effect on autophagy flux being most severe in aggregate-prone Des mutations such as DesL345P, DesL370P, and DesD399Y. RNA sequencing data confirmed the most prominent effect of these mutations on expression profile and, in particular, on autophagy-related genes. To verify CASA contribution to desmin aggregate formation, we suppressed CASA by knocking down Bag3 and demonstrated that it promoted aggregate formation and lead to downregulation of Vdac2 and Vps4a and upregulation of Lamp, Pink1, and Prkn. In conclusion, Des mutations showed a mutation-specific effect on autophagy flux in C2C12 cells with either a predominant impact on autophagosome maturation or on degradation and recycling processes. Aggregate-prone desmin mutations lead to the activation of basal autophagy level while suppressing the CASA pathway by knocking down Bag3 can promote desmin aggregate formation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Desmin mutations impact the autophagy flux in C2C12 cell in mutation-specific manner

Sukhareva,

Smolina,

Churkina

et al. 2023

Cell Tissue Res

Self Cite

View full text Add to dashboard Cite

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“…Peroxisome proliferator-activated receptor γ (PPARγ) inhibition downregulates BAG-3 and 14-3-3γ, which inhibits the stem-like qualities in GBM [194]. BAG-3 ko decreases 14-3-3ζ [195], suggesting a concurrent attenuation of AANAT stabilization by 14-3-3ζ. BAG-3 ko also increases PINK1 and parkin [196], indicating mitophagy upregulation, concurrent to suppression of the mitochondrial melatonergic pathway.…”

Section: Future Research Implicationsmentioning

confidence: 99%

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Anderson

2023

Exploration of Targeted Anti-Tumor Therapy

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A dysregulated circadian rhythm is significantly associated with cancer risk, as is aging. Both aging and circadian dysregulation show suppressed pineal melatonin, which is indicated in many studies to be linked to cancer risk and progression. Another independently investigated aspect of the circadian rhythm is the cortisol awakening response (CAR), which is linked to stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR and HPA axis activity are primarily mediated via activation of the glucocorticoid receptor (GR), which drives patterned gene expression via binding to the promotors of glucocorticoid response element (GRE)-expressing genes. Recent data shows that the GR can be prevented from nuclear translocation by the B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), which translocates the GR to mitochondria, where it can have diverse effects. Melatonin also suppresses GR nuclear translocation by maintaining the GR in a complex with heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, can upregulate BAG-1, suggesting that the dramatic 10-fold decrease in pineal melatonin from adolescence to the ninth decade of life will attenuate the capacity of night-time melatonin to modulate the effects of the early morning CAR. The interactions of pineal melatonin/BAG-1/Hsp90 with the CAR are proposed to underpin how aging and circadian dysregulation are associated with cancer risk. This may be mediated via differential effects of melatonin/BAG-1/Hsp90/GR in different cells of microenvironments across the body, from which tumors emerge. This provides a model of cancer pathogenesis that better integrates previously disparate bodies of data, including how immune cells are regulated by cancer cells in the tumor microenvironment, at least partly via the cancer cell regulation of the tryptophan-melatonin pathway. This has a number of future research and treatment implications.

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The Effect of Mutation of L345P in the Desmin Gene on the Process of Autophagy in Muscle Cells of the C2C12 Line

Cited by 2 publications

References 24 publications

Desmin mutations impact the autophagy flux in C2C12 cell in mutation-specific manner

Desmin mutations impact the autophagy flux in C2C12 cell in mutation-specific manner

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

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