Thyroid hormones control many aspects of physiology such as metabolism and thermogenesis. Because thyroid hormones control such crucial bodily functions, their levels in the body are tightly regulated. Hypo- and hyperthyroidism can result when the level of thyroid hormone is too low or too high, respectively, with potentially serious pathophysiological consequences. µ-Crystallin is an NADPH-regulated thyroid hormone binding protein. The protein is minimally expressed in the skeletal muscle of most people; however, some individuals express relatively high baseline levels of µ-crystallin. We generated a transgenic mouse, the Crym tg mouse, that expresses high levels of µ-crystallin in its skeletal muscle, in order to explore the consequences of expressing high levels, comparable to those seen in some humans. The Crym tg mouse expresses mouse µ-crystallin at levels 2.6-147.5-fold higher than control mice in their skeletal muscle. Consequently, intramuscular triiodothyronine (T3) levels are elevated ~190-fold in the tibialis anterior, while serum thyroxine levels are decreased by 1.2-fold. Crym tg mice have a decreased respiratory exchange ratio that corresponds to a 13.7% increase in fat utilization as an energy source. Female Crym tg mice gained weight faster on high fat or high simple carbohydrate diets. Gene ontology enrichment analysis of transcriptomic and proteomic data revealed alterations to the expression of genes associated with metabolism and fiber type, while the fiber sizes of Crym tg soleus muscle are significantly smaller than those of controls. Taken together, these results suggest that µ-crystallin may play a role in regulating metabolism, perhaps through the control of thyroid hormone in muscle. Thus, humans who naturally express higher levels of µ-crystallin in their skeletal muscle may have an altered metabolism, comparable to the Crym tg mice.