Journal article
BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease
International journal of molecular sciences, Vol.23(18), p.10715
09/15/2022
DOI: 10.3390/ijms231810715
PMCID: PMC9502689
PMID: 36142618
Abstract
Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, resulting in ischemic limb injuries. Individuals with diabetes and PAD typically have more severe ischemic limb injuries and limb amputations, but the mechanisms involved are poorly understood. Previously, we identified BAG3 as a gene within a mouse genetic locus termed limb salvage QTL1 on mouse chromosome 7 that determined the extent of limb necrosis following ischemic injury in C57Bl/6 mice. Whether BAG3 deficiency plays a role in the severe ischemic injury observed in diabetic PAD is not known. In vitro, we found simulated ischemia enhanced BAG3 expression in primary human skeletal muscle cells, whereas BAG3 knockdown increased necroptosis markers and decreased cell viability. In vivo, ischemic skeletal muscles from hind limbs of high-fat diet (HFD)-fed mice showed poor BAG3 expression compared to normal chow diet (NCD)-fed mice, and this was associated with increased limb amputations. BAG3 overexpression in ischemic skeletal muscles from hind limbs of HFD mice rescued limb amputation and improved autophagy, necroptosis, skeletal muscle function and regeneration. Therefore, BAG3 deficiency in ischemic skeletal muscles contributes to the severity of ischemic limb injury in diabetic PAD, likely through autophagy and necroptosis pathways.
Details
- Title: Subtitle
- BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease
- Creators
- Arul Mani - Roy J. and Lucille A. Carver College of MedicineKarthik DhanabalanVictor LaminThomas WongMadhu SinghAyotunde Dokun
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.23(18), p.10715
- DOI
- 10.3390/ijms231810715
- PMID
- 36142618
- PMCID
- PMC9502689
- NLM abbreviation
- Int J Mol Sci
- ISSN
- 1661-6596
- eISSN
- 1422-0067
- Publisher
- MDPI AG
- Grant note
- DOI: 10.13039/100000050, name: National Heart Lung and Blood Institute, award: R01 HL130399 to AO Dokun
- Language
- English
- Date published
- 09/15/2022
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984303000802771
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