Abstract
Skeletal muscle represents the largest pool of body zinc, however, little is known about muscle zinc homeostasis or muscle-specific zinc functions. Zip14 (Slc39a14) was the most highly expressed zinc transporter in skeletal muscle of mice in response to LPS-induced inflammation. We compared metabolic parameters of skeletal muscle from global Zip14 knockout (KO) and wild-type mice (WT). At basal steady state Zip14 KO mice exhibited a phenotype that included muscle wasting and metabolic endotoxemia. Microarray and qPCR analysis of gastrocnemius muscle RNA revealed that ablation of Zip14 produced increased muscle p-Mef2c, Hspb7 and miR-675-5p expression and increased p38 activation. ChIP assays showed enhanced binding of NF-kappa beta to the Mef2c promoter. In contrast, LPS-induced systemic inflammation enhanced Zip14-dependent zinc uptake by muscle, increased expression of Atrogin1 and MuRF1 and markedly reduced MyoD. These signatures of muscle atrophy and cachexia were not influenced by Zip14 ablation, however. LPS-induced miR-675-3p and -5p expression was Zip14-dependent. Collectively, these results with an integrative model are consistent with a Zip14 function in skeletal muscle at steady state that supports myogenesis through suppression of metabolic endotoxemia and that Zip14 ablation coincides with sustained activity of phosphorylated components of signaling pathways including p-Mef2c, which causes Hspb7-dependent muscle wasting.
Highlights
Skeletal muscle represents the body compartment in mammals with the largest proportion of total body zinc
Acute endotoxemia induced by liver11 and adipose tissue8 following endotoxin (LPS) increases ZIP14 expression in skeletal muscle
We hypothesized that zinc transport in skeletal muscle would be increased during inflammation through increased ZIP14, since expression of this metal transporter is increased in liver[11] and adipose tissue[8] following endotoxin (LPS) treatment and in liver during sepsis[12]
Summary
Skeletal muscle represents the body compartment in mammals with the largest proportion of total body zinc. Muscle TLR4 is activated by endotoxin (lipopolysaccharide; LPS) and causes altered substrate metabolism, including enhanced glucose utilization and decreased fatty acid oxidation. We conducted a screen of transcripts for all 24 of the ZnT and Zip family of zinc transporters using quantitative PCR (qPCR) in numerous tissues of mice following treatment with LPS7. Of the 24 transcripts studied, Zip[14] mRNA was the most highly up-regulated following LPS treatment in two tissues, i.e. white adipose tissue (WAT) and skeletal muscle. Based upon the recognized responsiveness of skeletal muscle to endotoxins and downstream metabolic events that occur as a result[3,9,10], we explored the phenotypic consequences of whole-body Zip[14] ablation (Zip[14] KO) in skeletal muscle. We report here that Zip[14] KO mice have muscle wasting as measured by physical and biochemical indices that are concurrent with inflammatory signatures
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