Matthew Bruss - Academia.edu (original) (raw)

Papers by Matthew Bruss

Research paper thumbnail of Differential translational control of 5' IRE-containing mRNA in response to dietary iron deficiency and acute iron overload

Metallomics : integrated biometal science, 2020

Iron regulatory proteins (IRPs) are iron-responsive RNA binding proteins that dictate changes in ... more Iron regulatory proteins (IRPs) are iron-responsive RNA binding proteins that dictate changes in cellular iron metabolism in animal cells by controlling the fate of mRNAs containing iron responsive elements (IREs). IRPs have broader physiological roles as some targeted mRNAs encode proteins with functions beyond iron metabolism suggesting hierarchical regulation of IRP-targeted mRNAs. We observe that the translational regulation of IRP-targeted mRNAs encoding iron storage (L- and H-ferritins) and export (ferroportin) proteins have different set-points of iron responsiveness compared to that for the TCA cycle enzyme mitochondrial aconitase. The ferritins and ferroportin mRNA were largely translationally repressed in the liver of rats fed a normal diet whereas mitochondrial aconitase mRNA is primarily polysome bound. Consequently, acute iron overload increases polysome association of H- and L-ferritin and ferroportin mRNAs while mitochondrial aconitase mRNA showed little stimulation. ...

Research paper thumbnail of Signaling from �1- and �2-adrenergic receptors is defined by differential interactions with PDE4

Research paper thumbnail of Effects of Physiologic, Metabolic and Molecular Adaptations to Calorie Restriction on Biomarkers of Longevity

Calorie restriction (CR), reducing caloric intake without malnutrition, increases lifespan and de... more Calorie restriction (CR), reducing caloric intake without malnutrition, increases lifespan and delays the onset of age-related diseases. Characterizing the underlying mechanisms that mediate the effects of calorie restriction on aging and lifespan will provide insight into the fundamental biology of aging, as well as guide research into the development of therapeutics for age-related diseases. It seems likely that some combination of physiologic, metabolic and molecular adaptations to CR lead to cellular responses that in-turn increase the longevity of the organism. Thus the goal of this thesis work was to combine a kinetic biomarker strategy with classic physiologic and molecular techniques to determine the role of physiologic adaptations, fat metabolism and molecular signaling on biomarkers of CR-induced longevity in mice. The data presented here demonstrate that CR leads to significant reductions in cell proliferation rates in keratinocytes, liver cells, mammary epithelial cells and splenic T-cells. These reductions in cell proliferation rates cannot be accounted for by reductions in food intake, energy expenditure, fat mass or body weight. In addition, the CR-induced reduction in cell proliferation is not dependent on Sirt1 expression, nor can it be mimicked by resveratrol treatment. However, reductions in cell proliferation rates were associated with a CRinduced increase in whole body fatty acid oxidation and have a strong negative correlation with circulating IGF-1 levels. Taken together these results suggest that increased reliance on fatty acid oxidation and reductions in IGF-1 signaling may be metabolic pathways that mediate the effects of CR on aging and longevity. These results also point to molecular mediators that can translate changes in substrate utilization to regulation of growth factor signaling as potential regulatory nodes necessary for the CR-induced effects on cell proliferation and longevity. I would like to acknowledge the help of mentors, colleagues, family and friends, for without their support this work would not be possible. My mentor throughout my PhD work, Marc Hellerstein, has been instrumental in guiding this research and making me a better scientist. His approach to conducting research will influence the rest of my career. My committee members, George Brooks and Andreas Stahl have challenged, guided and helped me excel. In addition, Sharon Fleming, Wally Wang and Hei Suk Sul have provided outstanding guidance. Nearly all of the ideas and studies presented here were a direct result of discussions and experiments conducted with Cyrus Khambatta and Airlia Thompson. These two colleagues are excellent researchers and I am truly grateful for their contributions. In addition, Max Ruby and DJ Rhook have been critical in helping me develop as a scientist. The work presented here would not have been possible without the amazing technical support

Research paper thumbnail of Fibroblast Growth Factor 21 Is Not Required for the Reductions in Circulating Insulin-Like Growth Factor-1 or Global Cell Proliferation Rates in Response to Moderate Calorie Restriction in Adult Mice

Research paper thumbnail of Calorie Restriction Does Not Increase Short-term or Long-term Protein Synthesis

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2013

Increased protein synthesis is proposed as a mechanism of lifespan extension during caloric restr... more Increased protein synthesis is proposed as a mechanism of lifespan extension during caloric restriction (CR). We hypothesized that CR does not increase protein synthesis in all tissues and protein fractions and that any increased protein synthesis with CR would be due to an increased anabolic effect of feeding. We used short-(4 hours) and long-term (6 weeks) methods to measure in vivo protein synthesis in lifelong ad libitum (AL) and CR mice. We did not detect an acute effect of feeding on protein synthesis while liver mitochondrial protein synthesis was lower in CR mice versus AL mice. Mammalian target of rapamycin (mTOR) signaling was repressed in liver and heart from CR mice indicative of energetic stress and suppression of growth. Our main findings were that CR did not increase rates of mixed protein synthesis over the long term or in response to acute feeding, and protein synthesis was maintained despite decreased mTOR signaling.

Research paper thumbnail of Desnutrin/ATGL Is Regulated by AMPK and Is Required for a Brown Adipose Phenotype

Research paper thumbnail of Integrative Analysis of a Cross-Loci Regulation Network Identifies App as a Gene Regulating Insulin Secretion from Pancreatic Islets

Research paper thumbnail of The effects of physiological adaptations to calorie restriction on global cell proliferation rates

AJP: Endocrinology and Metabolism, 2011

Calorie restriction (CR) reduces the rate of cell proliferation in mitotic tissues. It has been s... more Calorie restriction (CR) reduces the rate of cell proliferation in mitotic tissues. It has been suggested that this reduction in cell proliferation may mediate CR-induced increases in longevity. However, the mechanisms that lead to CR-induced reductions in cell proliferation rates remain unclear. To evaluate the CR-induced physiological adaptations that may mediate reductions in cell proliferation rates, we altered housing temperature and access to voluntary running wheels to determine the effects of food intake, energy expenditure, percent body fat, and body weight on proliferation rates of keratinocytes, liver cells, mammary epithelial cells, and splenic T-cells in C57BL/6 mice. We found that ∼20% CR led to a reduction in cell proliferation rates in all cell types. However, lower cell proliferation rates were not observed with reductions in 1) food intake and energy expenditure in female mice housed at 27°C, 2) percent body fat in female mice provided running wheels, or 3) body we...

Research paper thumbnail of Differential translational control of 5' IRE-containing mRNA in response to dietary iron deficiency and acute iron overload

Metallomics : integrated biometal science, 2020

Iron regulatory proteins (IRPs) are iron-responsive RNA binding proteins that dictate changes in ... more Iron regulatory proteins (IRPs) are iron-responsive RNA binding proteins that dictate changes in cellular iron metabolism in animal cells by controlling the fate of mRNAs containing iron responsive elements (IREs). IRPs have broader physiological roles as some targeted mRNAs encode proteins with functions beyond iron metabolism suggesting hierarchical regulation of IRP-targeted mRNAs. We observe that the translational regulation of IRP-targeted mRNAs encoding iron storage (L- and H-ferritins) and export (ferroportin) proteins have different set-points of iron responsiveness compared to that for the TCA cycle enzyme mitochondrial aconitase. The ferritins and ferroportin mRNA were largely translationally repressed in the liver of rats fed a normal diet whereas mitochondrial aconitase mRNA is primarily polysome bound. Consequently, acute iron overload increases polysome association of H- and L-ferritin and ferroportin mRNAs while mitochondrial aconitase mRNA showed little stimulation. ...

Research paper thumbnail of Signaling from �1- and �2-adrenergic receptors is defined by differential interactions with PDE4

Research paper thumbnail of Effects of Physiologic, Metabolic and Molecular Adaptations to Calorie Restriction on Biomarkers of Longevity

Calorie restriction (CR), reducing caloric intake without malnutrition, increases lifespan and de... more Calorie restriction (CR), reducing caloric intake without malnutrition, increases lifespan and delays the onset of age-related diseases. Characterizing the underlying mechanisms that mediate the effects of calorie restriction on aging and lifespan will provide insight into the fundamental biology of aging, as well as guide research into the development of therapeutics for age-related diseases. It seems likely that some combination of physiologic, metabolic and molecular adaptations to CR lead to cellular responses that in-turn increase the longevity of the organism. Thus the goal of this thesis work was to combine a kinetic biomarker strategy with classic physiologic and molecular techniques to determine the role of physiologic adaptations, fat metabolism and molecular signaling on biomarkers of CR-induced longevity in mice. The data presented here demonstrate that CR leads to significant reductions in cell proliferation rates in keratinocytes, liver cells, mammary epithelial cells and splenic T-cells. These reductions in cell proliferation rates cannot be accounted for by reductions in food intake, energy expenditure, fat mass or body weight. In addition, the CR-induced reduction in cell proliferation is not dependent on Sirt1 expression, nor can it be mimicked by resveratrol treatment. However, reductions in cell proliferation rates were associated with a CRinduced increase in whole body fatty acid oxidation and have a strong negative correlation with circulating IGF-1 levels. Taken together these results suggest that increased reliance on fatty acid oxidation and reductions in IGF-1 signaling may be metabolic pathways that mediate the effects of CR on aging and longevity. These results also point to molecular mediators that can translate changes in substrate utilization to regulation of growth factor signaling as potential regulatory nodes necessary for the CR-induced effects on cell proliferation and longevity. I would like to acknowledge the help of mentors, colleagues, family and friends, for without their support this work would not be possible. My mentor throughout my PhD work, Marc Hellerstein, has been instrumental in guiding this research and making me a better scientist. His approach to conducting research will influence the rest of my career. My committee members, George Brooks and Andreas Stahl have challenged, guided and helped me excel. In addition, Sharon Fleming, Wally Wang and Hei Suk Sul have provided outstanding guidance. Nearly all of the ideas and studies presented here were a direct result of discussions and experiments conducted with Cyrus Khambatta and Airlia Thompson. These two colleagues are excellent researchers and I am truly grateful for their contributions. In addition, Max Ruby and DJ Rhook have been critical in helping me develop as a scientist. The work presented here would not have been possible without the amazing technical support

Research paper thumbnail of Fibroblast Growth Factor 21 Is Not Required for the Reductions in Circulating Insulin-Like Growth Factor-1 or Global Cell Proliferation Rates in Response to Moderate Calorie Restriction in Adult Mice

Research paper thumbnail of Calorie Restriction Does Not Increase Short-term or Long-term Protein Synthesis

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2013

Increased protein synthesis is proposed as a mechanism of lifespan extension during caloric restr... more Increased protein synthesis is proposed as a mechanism of lifespan extension during caloric restriction (CR). We hypothesized that CR does not increase protein synthesis in all tissues and protein fractions and that any increased protein synthesis with CR would be due to an increased anabolic effect of feeding. We used short-(4 hours) and long-term (6 weeks) methods to measure in vivo protein synthesis in lifelong ad libitum (AL) and CR mice. We did not detect an acute effect of feeding on protein synthesis while liver mitochondrial protein synthesis was lower in CR mice versus AL mice. Mammalian target of rapamycin (mTOR) signaling was repressed in liver and heart from CR mice indicative of energetic stress and suppression of growth. Our main findings were that CR did not increase rates of mixed protein synthesis over the long term or in response to acute feeding, and protein synthesis was maintained despite decreased mTOR signaling.

Research paper thumbnail of Desnutrin/ATGL Is Regulated by AMPK and Is Required for a Brown Adipose Phenotype

Research paper thumbnail of Integrative Analysis of a Cross-Loci Regulation Network Identifies App as a Gene Regulating Insulin Secretion from Pancreatic Islets

Research paper thumbnail of The effects of physiological adaptations to calorie restriction on global cell proliferation rates

AJP: Endocrinology and Metabolism, 2011

Calorie restriction (CR) reduces the rate of cell proliferation in mitotic tissues. It has been s... more Calorie restriction (CR) reduces the rate of cell proliferation in mitotic tissues. It has been suggested that this reduction in cell proliferation may mediate CR-induced increases in longevity. However, the mechanisms that lead to CR-induced reductions in cell proliferation rates remain unclear. To evaluate the CR-induced physiological adaptations that may mediate reductions in cell proliferation rates, we altered housing temperature and access to voluntary running wheels to determine the effects of food intake, energy expenditure, percent body fat, and body weight on proliferation rates of keratinocytes, liver cells, mammary epithelial cells, and splenic T-cells in C57BL/6 mice. We found that ∼20% CR led to a reduction in cell proliferation rates in all cell types. However, lower cell proliferation rates were not observed with reductions in 1) food intake and energy expenditure in female mice housed at 27°C, 2) percent body fat in female mice provided running wheels, or 3) body we...