Exercise improved bone health in aging mice: a role of SIRT1 in regulating autophagy and osteogenic differentiation of BMSCs

Introduction This study was designed to investigate the effect of running exercise on improving bone health in aging mice and explore the role of the SIRT1 in regulating autophagy and osteogenic differentiation of Bone marrow Mesenchymal Stem Cells (BMSCs). Methods Twelve-month-old male C57BL/6J mice were used in this study as the aging model and were assigned to treadmill running exercise for eight weeks. Non-exercise male C57BL/6J mice of the same old were used as aging control and five-month-old mice were used as young controls. BMSCs were isolated from mice and subjected to mechanical stretching stimulation in vitro. Results The results showed that aging mice had lower bone mass, bone mineral density (BMD), and autophagy than young mice, while running exercise improved BMD and bone mass as well as upregulated autophagy in bone cells. Mechanical loading increased osteogenic differentiation and autophagy in BMSCs, and knockdown of SIRT1 in BMSCs demonstrated that SIRT1-regulated autophagy involved the mechanical loading activation of osteogenic differentiation. Conclusion Taken together, this study revealed that exercise improved bone health during aging by activating bone formation, which can be attributed to osteogenic differentiation of BMSCs through the activation of SIRT1-mediated autophagy. The mechanisms underlying this effect may involve mechanical loading.

[1]  Chenyu Zhu,et al.  Autophagy in Bone Remodeling: A Regulator of Oxidative Stress , 2022, Frontiers in Endocrinology.

[2]  Yun-A Shin,et al.  Moderate-Intensity Exercise Preserves Bone Mineral Density and Improves Femoral Trabecular Bone Microarchitecture in Middle-Aged Mice , 2022, Journal of bone metabolism.

[3]  Lingli Zhang,et al.  Effects of exercise on the expression of long non-coding RNAs in the bone of mice with osteoporosis , 2021, Experimental and therapeutic medicine.

[4]  Kang Yang,et al.  Bone Autophagy: A Potential Way of Exercise-Mediated Meg3/P62/Runx2 Pathway to Regulate Bone Formation in T2DM Mice , 2021, Diabetes, metabolic syndrome and obesity : targets and therapy.

[5]  F. Jiao,et al.  The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases , 2020, Oxidative medicine and cellular longevity.

[6]  Xiaowei Yu,et al.  Involvement of mechanosensitive ion channels in the effects of mechanical stretch induces osteogenic differentiation in mouse bone marrow mesenchymal stem cells , 2020, Journal of cellular physiology.

[7]  Kathryn Ferguson.  @Ferguson:  , 2020, American Ethnologist.

[8]  L. Louvet,et al.  Sirtuin 1 deficiency decreases bone mass and increases bone marrow adiposity in a mouse model of chronic energy deficiency. , 2020, Bone.

[9]  A. Qian,et al.  Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells , 2020, International journal of molecular sciences.

[10]  Zhihong Xie,et al.  P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head , 2020, Cell Death & Disease.

[11]  Lei Guo,et al.  The Role and Mechanism of SIRT1 in Resveratrol-regulated Osteoblast Autophagy in Osteoporosis Rats , 2019, Scientific Reports.

[12]  Lingli Zhang,et al.  MiR-214 Attenuates the Osteogenic Effects of Mechanical Loading on Osteoblasts , 2019, International Journal of Sports Medicine.

[13]  Hongbo He,et al.  MicroRNA‐130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate , 2019, Cell proliferation.

[14]  Jun Zou,et al.  The Effect of Exercise on the Prevention of Osteoporosis and Bone Angiogenesis , 2019, BioMed research international.

[15]  Bin Zhou,et al.  Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition. , 2018, Metabolism: clinical and experimental.

[16]  Zong-ping Luo,et al.  Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK‐SIRT1 signaling pathway , 2018, Free radical biology & medicine.

[17]  A. Infante,et al.  Osteogenesis and aging: lessons from mesenchymal stem cells , 2018, Stem Cell Research & Therapy.

[18]  Leisheng Jiang,et al.  Autophagy activation facilitates mechanical stimulation-promoted osteoblast differentiation and ameliorates hindlimb unloading-induced bone loss. , 2018, Biochemical and biophysical research communications.

[19]  Yan Jin,et al.  Autophagy controls mesenchymal stem cell properties and senescence during bone aging , 2017, Aging cell.

[20]  R. Eastell,et al.  Use of bone turnover markers in postmenopausal osteoporosis. , 2017, The lancet. Diabetes & endocrinology.

[21]  J. Davies,et al.  Concise Review: Musculoskeletal Stem Cells to Treat Age‐Related Osteoporosis , 2017, Stem cells translational medicine.

[22]  Binjie Gui,et al.  TRPV4 functions in flow shear stress induced early osteogenic differentiation of human bone marrow mesenchymal stem cells. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[23]  G. Pan,et al.  Alcohol Induces Cellular Senescence and Impairs Osteogenic Potential in Bone Marrow-Derived Mesenchymal Stem Cells , 2017, Alcohol and alcoholism.

[24]  Lingli Zhang,et al.  Cyclic compression stimulates osteoblast differentiation via activation of the Wnt/β-catenin signaling pathway. , 2017, Molecular medicine reports.

[25]  Xi Chen,et al.  Treadmill running exercise prevents senile osteoporosis and upregulates the Wnt signaling pathway in SAMP6 mice , 2016, Oncotarget.

[26]  S. Fanning,et al.  SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride , 2016, Oncotarget.

[27]  E. Ballestar,et al.  Autophagy maintains stemness by preventing senescence , 2016, Nature.

[28]  K. Davies,et al.  Oxidative stress response and Nrf2 signaling in aging. , 2015, Free radical biology & medicine.

[29]  K. Marycz,et al.  Physical Activity Increases the Total Number of Bone-Marrow-Derived Mesenchymal Stem Cells, Enhances Their Osteogenic Potential, and Inhibits Their Adipogenic Properties , 2015, Stem cells international.

[30]  J. Lippincott-Schwartz,et al.  Deacetylation of nuclear LC3 drives autophagy initiation under starvation. , 2015, Molecular cell.

[31]  Chunjuan Song,et al.  Autophagy induction is a survival response against oxidative stress in bone marrow-derived mesenchymal stromal cells. , 2014, Cytotherapy.

[32]  F. Cecconi,et al.  Oxidative stress and autophagy: the clash between damage and metabolic needs , 2014, Cell Death and Differentiation.

[33]  Myung-Shik Lee,et al.  Autophagy—a key player in cellular and body metabolism , 2014, Nature Reviews Endocrinology.

[34]  G. Lazzeri,et al.  HIGH-INTENSITY EXERCISE TRAINING INDUCES MORPHOLOGICAL AND BIOCHEMICAL CHANGES IN SKELETAL MUSCLES , 2013, Biology of sport.

[35]  E. Srour,et al.  The Changing Balance Between Osteoblastogenesis and Adipogenesis in Aging and its Impact on Hematopoiesis , 2013, Current Osteoporosis Reports.

[36]  K. Guan,et al.  Differential Regulation of Distinct Vps34 Complexes by AMPK in Nutrient Stress and Autophagy , 2013, Cell.

[37]  Michael L. Blackburn,et al.  Blueberry consumption prevents loss of collagen in bone matrix and inhibits senescence pathways in osteoblastic cells , 2012, AGE.

[38]  M. Sandri,et al.  Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles , 2011, Autophagy.

[39]  G. Hampson,et al.  The pathogenesis, diagnosis, investigation and management of osteoporosis , 2011, Journal of Clinical Pathology.

[40]  D. Rubinsztein,et al.  Autophagy and Aging , 2011, Cell.

[41]  E. Lewiecki,et al.  Osteoporosis , 2011, Annals of Internal Medicine.

[42]  T. Rachner,et al.  Osteoporosis: now and the future , 2011, The Lancet.

[43]  R. DePinho,et al.  Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in Cardiac Myocytes , 2010, Circulation research.

[44]  P. Brum,et al.  MAXIMAL LACTATE STEADY STATE IN RUNNING MICE: EFFECT OF EXERCISE TRAINING , 2007, Clinical and experimental pharmacology & physiology.

[45]  Majd Zayzafoon,et al.  RhoA and Cytoskeletal Disruption Mediate Reduced Osteoblastogenesis and Enhanced Adipogenesis of Human Mesenchymal Stem Cells in Modeled Microgravity , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[46]  D. Reinberg,et al.  Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. , 2004, Molecular cell.

[47]  T. Bateman,et al.  Bone development and age-related bone loss in male C57BL/6J mice. , 2003, Bone.

[48]  Sharmila Majumdar,et al.  Changes in Bone Structure and Mass With Advancing Age in the Male C57BL/6J Mouse , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[49]  C. Boz,et al.  The causes of aging and relationship between aging and health expenditure: An econometric causality analysis for Turkey. , 2019, The International journal of health planning and management.

[50]  P. Dineen,et al.  Now and in the future. , 1970, AORN journal.