Summary: | Chronic Mg<sup>2+</sup> deficiency is the underlying cause of a broad range of health dysfunctions. As 25% of body Mg<sup>2+</sup> is located in the skeletal muscle, Mg<sup>2+</sup> transport and homeostasis systems (MgTHs) in the muscle are critical for whole-body Mg<sup>2+</sup> homeostasis. In the present study, we assessed whether Mg<sup>2+</sup> deficiency alters muscle fiber characteristics and major pathways regulating muscle physiology. C57BL/6J mice received either a control, mildly, or severely Mg<sup>2+</sup>-deficient diet (0.1%; 0.01%; and 0.003% Mg<sup>2+</sup> wt/wt, respectively) for 14 days. Mg<sup>2+</sup> deficiency slightly decreased body weight gain and muscle Mg<sup>2+</sup> concentrations but was not associated with detectable variations in gastrocnemius muscle weight, fiber morphometry, and capillarization. Nonetheless, muscles exhibited decreased expression of several MgTHs (<i>MagT1</i>, <i>CNNM2</i>, <i>CNNM4</i>, and <i>TRPM6</i>). Moreover, TaqMan low-density array (TLDA) analyses further revealed that, before the emergence of major muscle dysfunctions, even a mild Mg<sup>2+</sup> deficiency was sufficient to alter the expression of genes critical for muscle physiology, including energy metabolism, muscle regeneration, proteostasis, mitochondrial dynamics, and excitation–contraction coupling.
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