Hepatocyte-specific deletion of Bis causes senescence in the liver without deteriorating hepatic function

Jung, Soonyoung; Yun, Hye Hyeon; Lim, Ji‐Hee; Lee, Dong‐Hyung; Seo, Sung Bin; Baek, Ji-Ye; Lee, Jeehan; Yoo, Kyu‐Cheul; Kim, Hyung-Min; Kim, Hong Lim; Lee, Jeong Hwa

doi:10.1016/j.bbrc.2022.06.046

Cited by 1 publication

(4 citation statements)

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“…In addition, alterations in the expression of HSPs were observed in Bis-SMKO mice; Western blotting revealed that HSPB8 expression was reduced, whereas HSPB5 and HSP70 expression was increased. The decrease in HSPB8, which was stabilized by BIS, was consistent with the results in heartor liver-specific Bis-KO mice [17][18][19]. In heart-specific Bis-KO mice, HSPB5 and HSP70 levels increased specifically in the insoluble fraction [17].…”

Section: Discussionsupporting

confidence: 88%

“…Disturbances in protein homeostasis have been previously suggested as a common critical finding in liver-or heart-specific Bis-KO mice [17][18][19]. Autophagy impairment was also observed in Bis-SMKO skeletal muscles, as shown by the accumulation of p62 and frequent observation of autophagic vacuoles by electron microscopy.…”

Section: Discussionmentioning

confidence: 79%

“…Considering that BIS depletion is restricted to fast-twitch muscle fibers in Bis-SMKO mice, it cannot also be excluded that BIS in satellite cells has the potential to drive muscle regeneration processes, including satellite cell proliferation and differentiation into myoblasts and, ultimately, fiber regeneration. In support of this possibility, we previously reported that BIS depletion in hepatocytes induces senescence, suggesting that BIS plays a role in maintaining liver regeneration potential [19]. Therefore, the role of BIS in skeletal muscle regeneration requires further investigation.…”

Section: Discussionmentioning

confidence: 82%

“…In the hearts and livers of heart-and liver-specific Bis-KO mice, the expression of p62 increased, while that of HSPB8 decreased [17,19]. Furthermore, p62 protein expression increased in the diaphragm and quadriceps of Bis-SMKO mice (Figures 3B and S2A).…”

Section: Accumulation Of Heat Shock Proteins (Hsps) and Z-disk Protei...mentioning

confidence: 93%

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Skeletal Muscle-Specific Bis Depletion Leads to Muscle Dysfunction and Early Death Accompanied by Impairment in Protein Quality Control

Jung

Riew

Yun

et al. 2023

IJMS

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Bcl-2-interacting cell death suppressor (BIS), also called BAG3, plays a role in physiological functions such as anti-apoptosis, cell proliferation, autophagy, and senescence. Whole-body Bis-knockout (KO) mice exhibit early lethality accompanied by abnormalities in cardiac and skeletal muscles, suggesting the critical role of BIS in these muscles. In this study, we generated skeletal muscle-specific Bis-knockout (Bis-SMKO) mice for the first time. Bis-SMKO mice exhibit growth retardation, kyphosis, a lack of peripheral fat, and respiratory failure, ultimately leading to early death. Regenerating fibers and increased intensity in cleaved PARP1 immunostaining were observed in the diaphragm of Bis-SMKO mice, indicating considerable muscle degeneration. Through electron microscopy analysis, we observed myofibrillar disruption, degenerated mitochondria, and autophagic vacuoles in the Bis-SMKO diaphragm. Specifically, autophagy was impaired, and heat shock proteins (HSPs), such as HSPB5 and HSP70, and z-disk proteins, including filamin C and desmin, accumulated in Bis-SMKO skeletal muscles. We also found metabolic impairments, including decreased ATP levels and lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the diaphragm of Bis-SMKO mice. Our findings highlight that BIS is critical for protein homeostasis and energy metabolism in skeletal muscles, suggesting that Bis-SMKO mice could be used as a therapeutic strategy for myopathies and to elucidate the molecular function of BIS in skeletal muscle physiology.

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