Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy.
BACKGROUND:High altitude associated hypobaric hypoxia is one of the cellular and environmental perturbation that alters proteostasis network and push the healthy cell towards loss of muscle mass. The present study has elucidated the robust proteostasis network and signaling mechanism for skeletal mu...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC6150520?pdf=render |
| _version_ | 1818192953094438912 |
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| author | Akanksha Agrawal Richa Rathor Ravi Kumar Geetha Suryakumar Lilly Ganju |
| author_facet | Akanksha Agrawal Richa Rathor Ravi Kumar Geetha Suryakumar Lilly Ganju |
| author_sort | Akanksha Agrawal |
| collection | DOAJ |
| description | BACKGROUND:High altitude associated hypobaric hypoxia is one of the cellular and environmental perturbation that alters proteostasis network and push the healthy cell towards loss of muscle mass. The present study has elucidated the robust proteostasis network and signaling mechanism for skeletal muscle atrophy under chronic hypobaric hypoxia (CHH). METHODS:Male Sprague Dawley rats were exposed to simulated hypoxia equivalent to a pressure of 282 torr for different durations (1, 3, 7 and 14 days). After CHH exposure, skeletal muscle tissue was excised from the hind limb of rats for biochemical analysis. RESULTS:Chronic hypobaric hypoxia caused a substantial increase in protein oxidation and exhibited a greater activation of ER chaperones, glucose-regulated protein-78 (GRP-78) and protein disulphide isomerase (PDI) till 14d of CHH. Presence of oxidized proteins triggered the proteolytic systems, 20S proteasome and calpain pathway which were accompanied by a marked increase in [Ca2+]. Upregulated Akt pathway was observed upto 07d of CHH which was also linked with enhanced glycogen synthase kinase-3β (GSk-3β) expression, a negative regulator of Akt. Muscle-derived cytokines, tumor necrosis factor-α (TNF-α), interferon-ϒ (IFN-©) and interleukin-1β (IL-1β) levels significantly increased from 07d onwards. CHH exposure also upregulated the expression of nuclear factor kappa-B (NF-κB) and E3 ligase, muscle atrophy F-box-1 (Mafbx-1/Atrogin-1) and MuRF-1 (muscle ring finger-1) on 07d and 14d. Further, severe hypoxia also lead to increase expression of ER-associated degradation (ERAD) CHOP/ GADD153, Ub-proteasome and apoptosis pathway. CONCLUSIONS:The disrupted proteostasis network was tightly coupled to degradative pathways, altered anabolic signaling, inflammation, and apoptosis under chronic hypoxia. Severe and prolonged hypoxia exposure affected the protein homeostasis which overwhelms the muscular system and tends towards skeletal muscle atrophy. |
| first_indexed | 2024-12-12T00:38:41Z |
| format | Article |
| id | doaj.art-5190cb6f3e994a2d954f8f811b0ec5fe |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T00:38:41Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5190cb6f3e994a2d954f8f811b0ec5fe2022-12-22T00:44:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01139e020428310.1371/journal.pone.0204283Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy.Akanksha AgrawalRicha RathorRavi KumarGeetha SuryakumarLilly GanjuBACKGROUND:High altitude associated hypobaric hypoxia is one of the cellular and environmental perturbation that alters proteostasis network and push the healthy cell towards loss of muscle mass. The present study has elucidated the robust proteostasis network and signaling mechanism for skeletal muscle atrophy under chronic hypobaric hypoxia (CHH). METHODS:Male Sprague Dawley rats were exposed to simulated hypoxia equivalent to a pressure of 282 torr for different durations (1, 3, 7 and 14 days). After CHH exposure, skeletal muscle tissue was excised from the hind limb of rats for biochemical analysis. RESULTS:Chronic hypobaric hypoxia caused a substantial increase in protein oxidation and exhibited a greater activation of ER chaperones, glucose-regulated protein-78 (GRP-78) and protein disulphide isomerase (PDI) till 14d of CHH. Presence of oxidized proteins triggered the proteolytic systems, 20S proteasome and calpain pathway which were accompanied by a marked increase in [Ca2+]. Upregulated Akt pathway was observed upto 07d of CHH which was also linked with enhanced glycogen synthase kinase-3β (GSk-3β) expression, a negative regulator of Akt. Muscle-derived cytokines, tumor necrosis factor-α (TNF-α), interferon-ϒ (IFN-©) and interleukin-1β (IL-1β) levels significantly increased from 07d onwards. CHH exposure also upregulated the expression of nuclear factor kappa-B (NF-κB) and E3 ligase, muscle atrophy F-box-1 (Mafbx-1/Atrogin-1) and MuRF-1 (muscle ring finger-1) on 07d and 14d. Further, severe hypoxia also lead to increase expression of ER-associated degradation (ERAD) CHOP/ GADD153, Ub-proteasome and apoptosis pathway. CONCLUSIONS:The disrupted proteostasis network was tightly coupled to degradative pathways, altered anabolic signaling, inflammation, and apoptosis under chronic hypoxia. Severe and prolonged hypoxia exposure affected the protein homeostasis which overwhelms the muscular system and tends towards skeletal muscle atrophy.http://europepmc.org/articles/PMC6150520?pdf=render |
| spellingShingle | Akanksha Agrawal Richa Rathor Ravi Kumar Geetha Suryakumar Lilly Ganju Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. PLoS ONE |
| title | Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. |
| title_full | Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. |
| title_fullStr | Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. |
| title_full_unstemmed | Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. |
| title_short | Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. |
| title_sort | role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy |
| url | http://europepmc.org/articles/PMC6150520?pdf=render |
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