μ-Crystallin in Mouse Skeletal Muscle Promotes a Shift from Glycolytic toward Oxidative Metabolism

• Published in: Current research in physiology Vol. 4; pp. 47 - 59
• Main Authors: Kinney, Christian J., O'Neill, Andrea, Noland, Kaila, Huang, Weiliang, Muriel, Joaquin, Lukyanenko, Valeriy, Kane, Maureen A., Ward, Christopher W., Collier, Alyssa F., Roche, Joseph A., McLenithan, John C., Reed, Patrick W., Bloch, Robert J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021; Elsevier
• Subjects: Glycolysis; Proteomics; RER; Research Paper; RNA-seq; Thyroid hormone; β-oxidation; Glycolysis; β-oxidation; Thyroid hormone; RNA-seq; RER; Proteomics
• ISSN: 2665-9441; 2665-9441
• DOI: 10.1016/j.crphys.2021.02.003

μ-Crystallin, encoded by the CRYM gene, binds the thyroid hormones, T3 and T4. Because T3 and T4 are potent regulators of metabolism and gene expression, and CRYM levels in human skeletal muscle can vary widely, we investigated the effects of overexpression of Crym. We generated transgenic mice, Crym tg, that expressed Crym protein specifically in skeletal muscle at levels 2.6–147.5 fold higher than in controls. Muscular functions, Ca2+ transients, contractile force, fatigue, running on treadmills or wheels, were not significantly altered, although T3 levels in tibialis anterior (TA) muscle were elevated ~190-fold and serum T4 was decreased 1.2-fold. Serum T3 and thyroid stimulating hormone (TSH) levels were unaffected. Crym transgenic mice studied in metabolic chambers showed a significant decrease in the respiratory exchange ratio (RER) corresponding to a 13.7% increase in fat utilization as an energy source compared to controls. Female but not male Crym tg mice gained weight more rapidly than controls when fed high fat or high simple carbohydrate diets. Although labeling for myosin heavy chains showed no fiber type differences in TA or soleus muscles, application of machine learning algorithms revealed small but significant morphological differences between Crym tg and control soleus fibers. RNA-seq and gene ontology enrichment analysis showed a significant shift towards genes associated with slower muscle function and its metabolic correlate, β-oxidation. Protein expression showed a similar shift, though with little overlap. Our study shows that μ-crystallin plays an important role in determining substrate utilization in mammalian muscle and that high levels of μ-crystallin are associated with a shift toward greater fat metabolism. [Display omitted] •μ-Crystallin (Crym) is expressed specifically in transgenic skeletal muscle at highly elevated levels.•T3 is increased ~190 fold in the Tibialis anterior muscle of Crym tg mice.•Small but significant changes in gene and protein expression in tg muscle towards a slow twitch, oxidative phenotype.•Metabolic studies show that Crym tg mice increase their use of fat as an energy source.•Female Crym tg mice gain weight faster on high fat or simple carbohydrate diets than controls.