Manganese influx and expression of ZIP8 is essential in primary myoblasts and contributes to activation of SOD2

Trace elements such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) function as enzyme cofactors and second messengers in cell signaling. Trace elements are emerging as key regulators of differentiation and development of mammalian tissues including blood, brain, and skeletal muscle. We pre...

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Bibliographic Details
Published in:	Metallomics Vol. 11; no. 6; pp. 114 - 1153
Main Authors:	Gordon, Shellaina J. V, Fenker, Daniel E, Vest, Katherine E, Padilla-Benavides, Teresita
Format:	Journal Article
Language:	English
Published:	England Royal Society of Chemistry 19-06-2019
Subjects:	Animals Apoptosis Brain Cation Transport Proteins - genetics Cation Transport Proteins - metabolism Cell death Cell proliferation Cells, Cultured Cofactors Copper Depletion Differentiation Enzyme Activation Gene Expression Gene Knockdown Techniques Hypertrophy Iron Mammals Manganese Manganese - metabolism Metals Mice, Inbred C57BL Modulators Muscles Musculoskeletal system Myoblasts Myoblasts - metabolism Phenotypes Regulators Second messengers Skeletal muscle Superoxide dismutase Superoxide Dismutase - metabolism Supplements Trace elements Trace metals Transport Zinc
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Summary:	Trace elements such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) function as enzyme cofactors and second messengers in cell signaling. Trace elements are emerging as key regulators of differentiation and development of mammalian tissues including blood, brain, and skeletal muscle. We previously reported an influx of Cu and dynamic expression of metal transporters during differentiation of skeletal muscle cells. Here, we demonstrate that during differentiation of skeletal myoblasts an increase of Mn, Fe and Zn also occurs. Interestingly the Mn increase is concomitant with increased Mn-dependent SOD2 levels. To better understand the Mn import pathway in skeletal muscle cells, we probed the functional relevance of the closely related proteins ZIP8 and ZIP14, which are implicated in Zn, Mn, and Fe transport. Partial depletion of ZIP8 severely impaired growth of myoblasts and led to cell death under differentiation conditions, indicating that ZIP8-mediated metal transport is essential in skeletal muscle cells. Moreover, knockdown of Zip8 impaired activity of the Mn-dependent SOD2. Growth defects were partially rescued only by Mn supplementation to the medium, suggesting additional functions for ZIP8 in the skeletal muscle lineage. Restoring wild type Zip8 into the knockdown cells rescued the proliferation and differentiation phenotypes. On the other hand, knockdown of Zip14 , had only a mild effect on myotube size, consistent with a role for ZIP14 in muscle hypertrophy. Simultaneous knockdown of both Zip8 and Zip14 further impaired differentiation and led cell death. This is the first report on the functional relevance of two members of the ZIP family of metal transporters in the skeletal muscle lineage, and further supports the paradigm that trace metal transporters are important modulators of mammalian tissue development. Trace elements such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) function as enzyme cofactors and second messengers in cell signaling.
Bibliography:	Electronic supplementary information (ESI) available. See DOI 10.1039/c8mt00348c ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1756-5901 1756-591X 1756-591X
DOI:	10.1039/c8mt00348c