BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease
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. Previous...
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/18/10715 |
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| author | Arul M. Mani Karthik Dhanabalan Victor Lamin Thomas Wong Madhu V. Singh Ayotunde O. Dokun |
| author_facet | Arul M. Mani Karthik Dhanabalan Victor Lamin Thomas Wong Madhu V. Singh Ayotunde O. Dokun |
| author_sort | Arul M. Mani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T23:44:19Z |
| format | Article |
| id | doaj.art-f01d476a5a6f4c4284772af59215641e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:44:19Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f01d476a5a6f4c4284772af59215641e2023-11-23T16:46:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181071510.3390/ijms231810715BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery DiseaseArul M. Mani0Karthik Dhanabalan1Victor Lamin2Thomas Wong3Madhu V. Singh4Ayotunde O. Dokun5Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADivision of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADivision of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADivision of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADivision of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADivision of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAPeripheral 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.https://www.mdpi.com/1422-0067/23/18/10715BAG3peripheral artery diseasediabetesautophagynecroptosis |
| spellingShingle | Arul M. Mani Karthik Dhanabalan Victor Lamin Thomas Wong Madhu V. Singh Ayotunde O. Dokun BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease International Journal of Molecular Sciences BAG3 peripheral artery disease diabetes autophagy necroptosis |
| title | BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease |
| title_full | BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease |
| title_fullStr | BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease |
| title_full_unstemmed | BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease |
| title_short | BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease |
| title_sort | bag3 attenuates ischemia induced skeletal muscle necroptosis in diabetic experimental peripheral artery disease |
| topic | BAG3 peripheral artery disease diabetes autophagy necroptosis |
| url | https://www.mdpi.com/1422-0067/23/18/10715 |
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