Metabolic benefits of methionine restriction in adult mice do not require functional methionine sulfoxide reductase A (MsrA)

Abstract

Methionine restriction (MR) extends lifespan and improves several markers of health in rodents. However, the proximate mechanisms of MR on these physiological benefits have not been fully elucidated. The essential amino acid methionine plays numerous biological roles and limiting its availability in the diet directly modulates methionine metabolism. There is growing evidence that redox regulation of methionine has regulatory control on some aspects of cellular function but interactions with MR remain largely unexplored. We tested the functional role of the ubiquitously expressed methionine repair enzyme methionine sulfoxide reductase A (MsrA) on the metabolic benefits of MR in mice. MsrA catalytically reduces both free and protein-bound oxidized methionine, thus playing a key role in its redox state. We tested the extent to which MsrA is required for metabolic effects of MR in adult mice using mice lacking MsrA. As expected, MR in control mice reduced body weight, altered body composition, and improved glucose metabolism. Interestingly, lack of MsrA did not impair the metabolic effects of MR on these outcomes. Moreover, females had blunted MR responses regardless of MsrA status compared to males. Overall, our data suggests that MsrA is not required for the metabolic benefits of MR in adult mice.

Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan inDrosophila

“…Interestingly, dimethyl sulfide (DMS) is reported to extend lifespan in C. elegans and in Drosophila in an MsrA -dependent manner 67 . In contrast, MsrA was reported to be nonessential for metabolic benefit of MetR in mice 68 . Whether MsrA is required for lifespan extension in other contexts in various organisms including mammals needs to be tested in the future.…”

Sulfur Amino Acid Restriction alters mitochondrial function depending on tissue, sex, and Methionine sulfoxide reductase A (MsrA) status.

“…Previously we showed that MsrA was not required to mediate the beneficial physiological effects of MR on glucose metabolism and body weight/composition. In these studies, we found that the lack of MsrA in mice manifested greater loss in lean and fat mass with MR, as well as larger improvements to glucose metabolism relative to normal diet compared to that in control mice 19 . These results suggest MsrA has an uncharacterized role in mediating or modulating MR.…”

“…We have described all husbandry conditions, the genetic mutant MsrA KO mouse, and diets used in this study in our previous publications 19 , 20 , 39 . All mice were maintained in the C57Bl/6J background and MR diets used were control diet (CD) (0.86% Met, TestDiet 578F w/0.86% MET – 5SFD) or MR (0.15% Met, 0% Cys, Test Diet 96D2, modified TestDiet 58B0).…”

“…Mice were fed each diet for approximately 2 months before the end of the study and were euthanized via CO 2 asphyxiation at which time tissues were collected for isolated mitochondrial studies. Tissue samples collected from an independent group of animals reported previously 19 were used for frozen mitochondrial assays and immunoblots.…”

“…Our group has explored the potential role that methionine sulfoxide reductase A (MsrA), a regulator of methionine oxidation/reduction (redox), may play in the molecular and physiological effects of MR 19 , 20 . The chemical structure of methionine is easily oxidized to methionine sulfoxide which has been shown to modify protein structure and function 21 – 25 .…”