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- Title
Skeletal Muscle-Specific Bis Depletion Leads to Muscle Dysfunction and Early Death Accompanied by Impairment in Protein Quality Control.
- Authors
Jung, Soon-Young; Riew, Tae-Ryong; Yun, Hye Hyeon; Lim, Ji Hee; Hwang, Ji-Won; Jung, Sung Won; Kim, Hong Lim; Lee, Jae-Seon; Lee, Mun-Yong; Lee, Jeong-Hwa
- Abstract
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.
- Subjects
EARLY death; SKELETAL muscle physiology; HEAT shock proteins; QUALITY control; BISPECIFIC antibodies; SUPPRESSOR cells; HOMEOSTASIS
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 11, p9635
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms24119635