A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation
Muscle atrophy is defined as the progressive degeneration or shrinkage of myocytes and is triggered by factors such as aging, cancer, injury, inflammation, and immobilization. Considering the total amount of body iron stores and its crucial role in skeletal muscle, myocytes may have their own iron r...
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MDPI AG
2022-09-01
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| author | Dae Keun Suh Won-Young Lee Woo Jin Yeo Bong Soo Kyung Koo Whang Jung Hye Kyung Seo Yong-Soo Lee Dong Won Suh |
| author_facet | Dae Keun Suh Won-Young Lee Woo Jin Yeo Bong Soo Kyung Koo Whang Jung Hye Kyung Seo Yong-Soo Lee Dong Won Suh |
| author_sort | Dae Keun Suh |
| collection | DOAJ |
| description | Muscle atrophy is defined as the progressive degeneration or shrinkage of myocytes and is triggered by factors such as aging, cancer, injury, inflammation, and immobilization. Considering the total amount of body iron stores and its crucial role in skeletal muscle, myocytes may have their own iron regulation mechanism. Although the detrimental effects of iron overload or iron deficiency on muscle function have been studied, the molecular mechanism of iron-dependent muscle atrophy has not been elucidated. Using human muscle tissues and in the mouse rotator cuff tear model, we confirmed an association between injury-induced iron depletion in myocytes and muscle atrophy. In differentiated C2C12 myotubes, the effects of iron deficiency on myocytes and the molecular mechanism of muscle atrophy by iron deficiency were evaluated. Our study revealed that the lower iron concentration in injured muscle was associated with the upregulation of ferroportin, an iron exporter that transports iron out of cells. Ferroportin expression was increased by hypoxia-inducible factor 1α (HIF1α), which is activated by muscle injury, and its expression is controlled by HIF1 inhibitor treatment. Iron deprivation caused myocyte loss and a marked depletion of mitochondrial membrane potential leading to muscle atrophy, together with increased levels of myostatin, the upstream regulator of atrogin1 and muscle RING-finger protein-1 (MuRF1). Myostatin expression under iron deficiency was mediated by an orphan nuclear receptor, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome (DAX1). |
| first_indexed | 2024-03-10T00:27:07Z |
| format | Article |
| id | doaj.art-e431bd0a579848ff9f39805b89414b37 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T00:27:07Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e431bd0a579848ff9f39805b89414b372023-11-23T15:33:20ZengMDPI AGCells2073-44092022-09-011118285310.3390/cells11182853A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron DeprivationDae Keun Suh0Won-Young Lee1Woo Jin Yeo2Bong Soo Kyung3Koo Whang Jung4Hye Kyung Seo5Yong-Soo Lee6Dong Won Suh7Department of Orthopedic Surgery, Korea University Anam Hospital, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, KoreaHand and Foot Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, KoreaJoint Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, KoreaJoint Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, KoreaJoint Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, KoreaResearch Center for Cartilage Regeneration, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, KoreaResearch Center for Cartilage Regeneration, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, KoreaJoint Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, KoreaMuscle atrophy is defined as the progressive degeneration or shrinkage of myocytes and is triggered by factors such as aging, cancer, injury, inflammation, and immobilization. Considering the total amount of body iron stores and its crucial role in skeletal muscle, myocytes may have their own iron regulation mechanism. Although the detrimental effects of iron overload or iron deficiency on muscle function have been studied, the molecular mechanism of iron-dependent muscle atrophy has not been elucidated. Using human muscle tissues and in the mouse rotator cuff tear model, we confirmed an association between injury-induced iron depletion in myocytes and muscle atrophy. In differentiated C2C12 myotubes, the effects of iron deficiency on myocytes and the molecular mechanism of muscle atrophy by iron deficiency were evaluated. Our study revealed that the lower iron concentration in injured muscle was associated with the upregulation of ferroportin, an iron exporter that transports iron out of cells. Ferroportin expression was increased by hypoxia-inducible factor 1α (HIF1α), which is activated by muscle injury, and its expression is controlled by HIF1 inhibitor treatment. Iron deprivation caused myocyte loss and a marked depletion of mitochondrial membrane potential leading to muscle atrophy, together with increased levels of myostatin, the upstream regulator of atrogin1 and muscle RING-finger protein-1 (MuRF1). Myostatin expression under iron deficiency was mediated by an orphan nuclear receptor, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome (DAX1).https://www.mdpi.com/2073-4409/11/18/2853muscle atrophyironhypoxia-inducible factor 1ferroportinmyostatintranscription factor |
| spellingShingle | Dae Keun Suh Won-Young Lee Woo Jin Yeo Bong Soo Kyung Koo Whang Jung Hye Kyung Seo Yong-Soo Lee Dong Won Suh A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation Cells muscle atrophy iron hypoxia-inducible factor 1 ferroportin myostatin transcription factor |
| title | A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation |
| title_full | A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation |
| title_fullStr | A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation |
| title_full_unstemmed | A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation |
| title_short | A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation |
| title_sort | novel muscle atrophy mechanism myocyte degeneration due to intracellular iron deprivation |
| topic | muscle atrophy iron hypoxia-inducible factor 1 ferroportin myostatin transcription factor |
| url | https://www.mdpi.com/2073-4409/11/18/2853 |
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