Skeletal muscle atrophy and whole-body glucose intolerance are consequences of muscle disuse associated with conditions leading to prolonged bed rest. Nutritional supplementation with chromium has been shown to prevent weight loss and improve glucose tolerance in malnourished subjects on long-term total parenteral nutrition. The objective of this study was to evaluate the effect of oral supplementation with a novel chromium complex, chromium (d-phenylalanine)(3) [Cr(d-phe)(3)] at 45 microg/kg/day for 5 weeks, on skeletal muscle atrophy and glucose intolerance in a hindlimb suspension mouse model. Hindlimb-suspended mice exhibited reduced skeletal muscle fiber size and enhanced whole-body glucose intolerance, both of which were reversed by chromium treatment. The inhibition of skeletal muscle atrophy by chromium was associated with reductions in the ubiquitination ligase atrogin-1/muscle atrophy F-box, which is elevated in hindlimb-suspended mice. Neither hindlimb suspension nor chromium treatment altered the protein levels of the myostatin, phospho-Forkhead box O-1 and mammalian target of rapamycin. Chromium-treated animals exhibited elevated Akt (Homo sapiens v-akt murine thymoma viral oncogene homolog) phosphorylation in their skeletal muscle, with no change observed in the levels of activated JNK (c-Jun N-terminal kinase). Thus, these data suggest that nutritional supplementation with chromium may have potential therapeutic benefits in minimizing skeletal muscle atrophy associated with long periods of muscle disuse.