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Cellular, Molecular and Metabolic Variation Resulting from Skeletal-Muscle Specific High-Expression of the Thyroid Hormone Binding Protein mu-Crystallin are Sex-Specific and Diet-Dependent
Abstract
The prevalence of obesity continues to rise globally while traditional modalities such as dietary change, increase in physical activity, and behavioral therapy are often insufficient countermeasures. As such additional treatment modalities are increasingly necessary. Pharmacotherapeutics have been developed and are proven to be key agents to address impaired cellular and molecular processes in certain obese individuals, generally targeting modulation of leptin and its associated signaling pathways. An additional potential target are thyroid hormones as they are potent regulators of metabolism. It is known that the thyroid hormone binding protein, mu-crystallin, is expressed in high levels in approximately 20% of the human population, and since skeletal muscle is a major metabolic organ, we sought to determine the role that skeletal-muscle specific high-expression (SM-HE) of mu-crystallin plays in the modulation of murine whole-body metabolism. Our work uses a transgenic line of mice, Crym-tg, that have (SM-HE) of mu-crystallin comparable to levels seen in high-expressing humans. Our previous work documented minor physiological and functional phenotypic factors of male Crym-tg mice on standard chow (of note, we did not evaluate female mice), but that there was a small but significant shift (13.7%) towards fatty acid metabolism when compared to controls as measured via indirect calorimetry of CLAMS cages. We also documented a ~192-fold increase in intracellular T3 levels in the tibialis anterior of Crym-tg mice. These findings were also consistent on the transcriptomic and proteomic levels with an increase in expression of slower contractile and oxidative metabolism genes, with a decrease in glycolytic and fast contractile genes. This body of work further characterizes the role of SM-HE of mu-crystallin in the context of the Crym-tg line. To do so, we evaluated both male and female Crym-tg mice following a low- or high-fat diet intervention with glucose tolerance and insulin tolerance testing, indirect calorimetry metabolic analysis, and transcriptomic and proteomic based measures. We posited that both male and female Crym-tg mice would demonstrate a protection in the traditional high-fat diet-induced obesity phenotype with minimal differences in the low-fat diet cohort. Interestingly, we found diet- and sex-specific differences across the cohorts in a variety of parameters including decreased lean mass in males on low-fat diet and in females on high-fat diet, sex- and diet-specific changes in gene expression relating to various cellular pathways including branched-chain amino acid catabolism, and fiber cross-sectional area. However, we could not attribute these changes to indirect calorimetry data. Noting that the indirect calorimetry did not account for the utilization of protein as an energy source, we shifted our focus to mu-crystallin’s other known functional role as a ketimine reductase. These data, along with our findings of significant changes in expression of genes relating to branched-chain amino acid metabolism, lend credence that the alterations in lean mass and other parameters are likely primarily due to mu-crystallin’s role as a ketimine reductase. Further work is needed to determine the role that sex-hormones contribute to the sexually dimorphic results we describe, especially since the mediation of thyroid hormones effects are known to be influenced by estrogen.Description
University of Maryland, Baltimore, School of Medicine, Ph.D. 2024.Keyword
Diet, High-FatDiet, Fat-Restricted
Calorimetry, Indirect
Metabolism
mu-Crystallins
Sex Factors
Thyroid Hormones