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Methionine-Restricted Diet Increases miRNAs That Can Target RUNX2 Expression and Alters Bone Structure in Young Mice
Jason Plummer1, Miri Park1, Frantz Perodin1
1Orentreich Foundation for the Advancement of Science, Inc., Cold Spring, New York.
Abstract:
Dietary methionine restriction (MR) increases longevity and improves healthspan in rodent models. Young male C57BL/6J mice were placed on MR to assess effects on bone structure and formation. Mice were fed diets containing 0.86% or 0.12% methionine for 5 weeks. Fasting blood plasma was analyzed for metabolic and bone-related biomarkers. Tibiae were analyzed by histomorphometry, while femurs were analyzed by micro-CT and biomechanically using 4-point bending. MR mice had reduced plasma glucose and insulin, while FGF21 and FGF23 increased. Plasma levels of osteocalcin and osteoprotegrin were unaffected, but sclerostin and procollagen I decreased. MR induced bone marrow fat accretion, antithetical to the reduced fat depots seen throughout the body. Cortical bone showed significant decreases in Bone Tissue Density (BTD). In trabecular bone, mice had decreased BTD, bone surface, trabecula and bone volume, and trabecular thickness.. Biomechanical testing showed that on MR, bones were significantly less stiff and had reduced maximum load and total work, suggesting greater fragility. Reduced expression of RUNX2 occurred in bone marrow of MR mice. These results suggest that MR alters bone remodeling and apposition. In MR mice, miR-31 in plasma and liver, and miR-133a, miR-335-5p, and miR-204 in the bone marrow was elevated. These miRNAs were shown previously to target and regulate Osterix and RUNX2 in bone, which could inhibit osteoblast differentiation and function. Therefore, dietary MR in young animals alters bone structure by increasing miRNAs in bone and liver that can target RUNX2. J. Cell. Biochem. 118: 31-42, 2017. © 2016 Wiley Periodicals, Inc.
Insights
Dietary methionine restriction (MR) in young mice negatively impacts bone structure and strength. This longevity intervention increases specific microRNAs (miRNAs) that may inhibit bone formation, leading to more fragile bones.
Area of Science:
- Bone Biology
- Metabolic Regulation
- Aging Research
Background:
- Dietary methionine restriction (MR) is known to extend lifespan and improve healthspan in rodent models.
- Understanding the systemic effects of MR on various tissues, including bone, is crucial for evaluating its therapeutic potential.
Purpose of the Study:
- To investigate the impact of dietary methionine restriction on bone structure, formation, and remodeling in young male mice.
- To identify potential molecular mechanisms, including microRNA regulation, underlying MR-induced bone alterations.
Main Methods:
- Young male C57BL/6J mice were subjected to dietary methionine restriction (0.12% methionine) or control diet (0.86% methionine) for 5 weeks.
- Analyses included plasma biomarker assessment, bone histomorphometry, micro-computed tomography (micro-CT), biomechanical testing, and gene/microRNA expression profiling.
Main Results:
- Methionine restriction led to reduced plasma glucose and insulin, with increased FGF21 and FGF23.
- Bone analysis revealed decreased cortical and trabecular bone tissue density, reduced bone volume, and impaired biomechanical properties, indicating increased fragility.
- Elevated levels of specific microRNAs (e.g., miR-31, miR-133a) were observed in plasma, liver, and bone marrow, potentially targeting RUNX2 and Osterix, key regulators of osteoblast differentiation.
Conclusions:
- Dietary methionine restriction in young animals significantly alters bone structure and biomechanical properties, leading to increased bone fragility.
- The observed changes in bone are associated with altered metabolic markers and an increase in specific microRNAs in bone and liver, suggesting a novel regulatory pathway impacting bone formation.
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