Hallmarks of frailty and osteosarcopenia in prematurely aged PolgA(D257A/D257A) mice

Frailty is a geriatric syndrome characterized by increased susceptibility to adverse health outcomes. One major determinant thereof is the gradual weakening of the musculoskeletal system and the associated osteosarcopenia. To improve our understanding of the underlying pathophysiology and, more importantly, to test potential interventions aimed at counteracting frailty suitable animal models are needed. Here, we report the relevance of a mouse model of accelerated aging (PolgA(D257A/D257A)) as a model for frailty and osteosarcopenia. The longitudinal assessment of the clinical mouse frailty index showed that PolgA(D257A/D257A) mice accumulated health deficits at a higher rate compared to wild type littermates (PolgA(+/+), WT). Concomitantly, PolgA(D257A/D257A) mice displayed progressive musculoskeletal deterioration such as reduced bone and muscle mass as well as impaired functionality thereof. Specifically, PolgA(D257A/D257A) had lower grip-strength and concentric muscle forces as well as reduced bone turnover as assessed by longitudinal micro-CT. In addition, PolgA(D257A/D257A) mutation altered the sensitivity to anabolic stimuli in skeletal muscle, muscle progenitors and bone. While, compared to WT, PolgA(D257A/D257A) caudal vertebrae were not responsive to a cyclic loading regime, PolgA(D257A/D257A) muscles were hypersensitive to eccentric contractions as well as leucine administration, shown by larger downstream signaling response of the mechanistic target of rapamycin complex 1 (mTORC1). However, myogenic progenitors cultured in vitro showed severe anabolic resistance to leucine and robust impairments in cell proliferation. Overall, PolgA(D257A/D257A) mutation leads to hallmarks of age-related frailty and osteosarcopenia as observed in humans and thus, provides a powerful model to better understand the relationship between frailty and the aging musculoskeletal system.

[1]  R. de Cabo,et al.  A toolbox for the longitudinal assessment of healthspan in aging mice , 2020, Nature Protocols.

[2]  G. D’Hulst,et al.  Voluntary Resistance Running as a Model to Induce mTOR Activation in Mouse Skeletal Muscle , 2019, Front. Physiol..

[3]  D. Sinclair,et al.  Voluntary exercise normalizes the proteomic landscape in muscle and brain and improves the phenotype of progeroid mice , 2019, Aging cell.

[4]  D. Glass,et al.  Partial Inhibition of mTORC1 in Aged Rats Counteracts the Decline in Muscle Mass and Reverses Molecular Signaling Associated with Sarcopenia , 2019, Molecular and Cellular Biology.

[5]  I. Bellantuono,et al.  Geroprotectors: A role in the treatment of frailty , 2019, Mechanisms of Ageing and Development.

[6]  Freddie H. Fu,et al.  Rapamycin Rescues Age-Related Changes in Muscle-Derived Stem/Progenitor Cells from Progeroid Mice , 2019, Molecular Therapy: Methods & Clinical Development.

[7]  Lucia H. S. Cevidanes,et al.  Novel application and validation of in vivo micro-CT to study bone modelling in 3D. , 2019, Orthodontics & craniofacial research.

[8]  S. Sadayappan,et al.  Myonuclear accretion is a determinant of exercise-induced remodeling in skeletal muscle , 2019, eLife.

[9]  J. Shrager,et al.  mTORC1 underlies age‐related muscle fiber damage and loss by inducing oxidative stress and catabolism , 2019, Aging cell.

[10]  T. Hornberger,et al.  Resistance Exercise-Induced Hypertrophy: A Potential Role for Rapamycin-Insensitive mTOR. , 2019, Exercise and sport sciences reviews.

[11]  S. Howlett,et al.  Rodent models of frailty and their application in preclinical research , 2019, Mechanisms of Ageing and Development.

[12]  Alicia Mayeuf-Louchart,et al.  MuscleJ: a high-content analysis method to study skeletal muscle with a new Fiji tool , 2018, Skeletal Muscle.

[13]  Richard E Brown,et al.  Sex Differences in Healthspan Predict Lifespan in the 3xTg-AD Mouse Model of Alzheimer’s Disease , 2018, Front. Aging Neurosci..

[14]  J. Krützfeldt,et al.  Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control , 2018, Journal of cachexia, sarcopenia and muscle.

[15]  I. Bellantuono.  Find drugs that delay many diseases of old age , 2018, Nature.

[16]  S. Anker,et al.  Ethical guidelines for publishing in the journal of cachexia, sarcopenia and muscle: update 2017 , 2017, Journal of cachexia, sarcopenia and muscle.

[17]  G. Duque,et al.  Osteosarcopenia: A new geriatric syndrome. , 2017, Australian family physician.

[18]  Mee-Sup Yoon,et al.  mTOR as a Key Regulator in Maintaining Skeletal Muscle Mass , 2017, Front. Physiol..

[19]  S. Larsson,et al.  Leisure‐Time Physical Activity and Risk of Fracture: A Cohort Study of 66,940 Men and Women , 2017, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  H. Hirschfeld,et al.  Osteosarcopenia: where bone, muscle, and fat collide , 2017, Osteoporosis International.

[21]  R. Palme,et al.  Severity classification of repeated isoflurane anesthesia in C57BL/6JRj mice—Assessing the degree of distress , 2017, PloS one.

[22]  F. McGuigan,et al.  Musculoskeletal health and frailty. , 2017, Best practice & research. Clinical rheumatology.

[23]  S. Walrand,et al.  Sarcopenia in older mice is characterized by a decreased anabolic response to a protein meal. , 2017, Archives of gerontology and geriatrics.

[24]  A. Mitnitski,et al.  A Frailty Index Based On Deficit Accumulation Quantifies Mortality Risk in Humans and in Mice , 2017, Scientific Reports.

[25]  S. Howlett,et al.  Development of a Rat Clinical Frailty Index , 2017, The journals of gerontology. Series A, Biological sciences and medical sciences.

[26]  Weiguo Zou,et al.  Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice* , 2016, The Journal of Biological Chemistry.

[27]  Freddie H. Fu,et al.  mTOR signaling plays a critical role in the defects observed in muscle‐derived stem/progenitor cells isolated from a murine model of accelerated aging , 2016, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[28]  H. Cohen,et al.  Physical Resilience in Older Adults: Systematic Review and Development of an Emerging Construct. , 2016, The journals of gerontology. Series A, Biological sciences and medical sciences.

[29]  R. de Cabo,et al.  Impact of Longevity Interventions on a Validated Mouse Clinical Frailty Index. , 2016, The journals of gerontology. Series A, Biological sciences and medical sciences.

[30]  Stuart M Phillips,et al.  Skeletal muscle satellite cells are located at a closer proximity to capillaries in healthy young compared with older men , 2016, Journal of cachexia, sarcopenia and muscle.

[31]  L. Deldicque,et al.  Aging Reduces the Activation of the mTORC1 Pathway after Resistance Exercise and Protein Intake in Human Skeletal Muscle: Potential Role of REDD1 and Impaired Anabolic Sensitivity , 2016, Nutrients.

[32]  J. Klein-Nulend,et al.  Aging related ER stress is not responsible for anabolic resistance in mouse skeletal muscle. , 2015, Biochemical and biophysical research communications.

[33]  Ralph Müller,et al.  Bone adaptation to cyclic loading in murine caudal vertebrae is maintained with age and directly correlated to the local micromechanical environment. , 2015, Journal of biomechanics.

[34]  F. Gómez,et al.  Comprehensive nutritional status in sarco-osteoporotic older fallers , 2015, The journal of nutrition, health & aging.

[35]  M. Parker.  The altered fate of aging satellite cells is determined by signaling and epigenetic changes , 2015, Front. Genet..

[36]  M. Tarnopolsky,et al.  Defects in mitochondrial DNA replication and oxidative damage in muscle of mtDNA mutator mice. , 2014, Free radical biology & medicine.

[37]  Georg N Duda,et al.  Mineralizing surface is the main target of mechanical stimulation independent of age: 3D dynamic in vivo morphometry. , 2014, Bone.

[38]  Matthew J Silva,et al.  Aging diminishes lamellar and woven bone formation induced by tibial compression in adult C57BL/6. , 2014, Bone.

[39]  R. Yu,et al.  Incremental predictive value of sarcopenia for incident fracture in an elderly Chinese cohort: results from the Osteoporotic Fractures in Men (MrOs) Study. , 2014, Journal of the American Medical Directors Association.

[40]  M. Crotty,et al.  Musculoskeletal health, frailty and functional decline. , 2014, Best practice & research. Clinical rheumatology.

[41]  J. Arbeit,et al.  WNT7B Promotes Bone Formation in part through mTORC1 , 2014, PLoS genetics.

[42]  Robert A. Rose,et al.  A Clinical Frailty Index in Aging Mice: Comparisons With Frailty Index Data in Humans , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[43]  O. Gavrilova,et al.  Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. , 2013, Cell reports.

[44]  M. Sandri,et al.  Mechanisms regulating skeletal muscle growth and atrophy , 2013, The FEBS journal.

[45]  T. Hornberger,et al.  Eccentric contractions increase the phosphorylation of tuberous sclerosis complex‐2 (TSC2) and alter the targeting of TSC2 and the mechanistic target of rapamycin to the lysosome , 2013, The Journal of physiology.

[46]  Georg N Duda,et al.  Diminished response to in vivo mechanical loading in trabecular and not cortical bone in adulthood of female C57Bl/6 mice coincides with a reduction in deformation to load. , 2013, Bone.

[47]  T. Burkholder,et al.  High-frequency electrical stimulation reveals a p38–mTOR signaling module correlated with force–time integral , 2013, Journal of Experimental Biology.

[48]  T. Prolla,et al.  Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice. , 2013, Mitochondrion.

[49]  L. Deldicque,et al.  Effect of acute environmental hypoxia on protein metabolism in human skeletal muscle , 2013, Acta physiologica.

[50]  A. Musarò,et al.  Age-dependent alteration in muscle regeneration: the critical role of tissue niche , 2013, Biogerontology.

[51]  Michael G. Garelick,et al.  Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival , 2012, Science Translational Medicine.

[52]  S. Xuan,et al.  Matrix IGF-1 regulates bone mass by activation of mTOR in mesenchymal stem cells , 2012, Nature Medicine.

[53]  Matthew J. Silva,et al.  Tibial Loading Increases Osteogenic Gene Expression and Cortical Bone Volume in Mature and Middle-Aged Mice , 2012, PloS one.

[54]  D. Sabatini,et al.  mTOR Signaling in Growth Control and Disease , 2012, Cell.

[55]  K. Rockwood,et al.  A procedure for creating a frailty index based on deficit accumulation in aging mice. , 2012, The journals of gerontology. Series A, Biological sciences and medical sciences.

[56]  T. Prolla,et al.  Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. , 2012, Cell metabolism.

[57]  Ralph Müller,et al.  Mouse tail vertebrae adapt to cyclic mechanical loading by increasing bone formation rate and decreasing bone resorption rate as shown by time-lapsed in vivo imaging of dynamic bone morphometry. , 2011, Bone.

[58]  Stuart M Phillips,et al.  Skeletal muscle protein metabolism in the elderly: Interventions to counteract the 'anabolic resistance' of ageing , 2011, Nutrition & metabolism.

[59]  R Bogaerts,et al.  Development of micro-CT protocols for in vivo follow-up of mouse bone architecture without major radiation side effects. , 2011, Bone.

[60]  Timothy M Wright,et al.  Tibial compression is anabolic in the adult mouse skeleton despite reduced responsiveness with aging. , 2011, Bone.

[61]  M. Wylezinska-Arridge,et al.  Imaging technologies for preclinical models of bone and joint disorders , 2011, EJNMMI research.

[62]  R. Wolfe,et al.  The anabolic response to resistance exercise and a protein-rich meal is not diminished by age , 2011, The journal of nutrition, health & aging.

[63]  L. Fried,et al.  Severe osteopenia and osteoporosis, sarcopenia, and frailty status in community-dwelling older women: results from the Women's Health and Aging Study (WHAS) II. , 2011, Bone.

[64]  E. Volpi,et al.  Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis , 2011, Skeletal Muscle.

[65]  Ralph Müller,et al.  In vivo micro-computed tomography allows direct three-dimensional quantification of both bone formation and bone resorption parameters using time-lapsed imaging. , 2011, Bone.

[66]  Gregory C Kujoth,et al.  Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice , 2011, Proceedings of the National Academy of Sciences.

[67]  Ralph Müller,et al.  Guidelines for assessment of bone microstructure in rodents using micro–computed tomography , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[68]  Matthew J. Silva,et al.  Age-Related Changes in Bone Structure and Strength in Female and Male BALB/c Mice , 2010, Calcified Tissue International.

[69]  Wen-Lu Weng,et al.  Solubilities of amino acids in water at various pH values under 298.15 K , 2009 .

[70]  R. Wolfe,et al.  A moderate serving of high-quality protein maximally stimulates skeletal muscle protein synthesis in young and elderly subjects. , 2009, Journal of the American Dietetic Association.

[71]  T. Hornberger,et al.  The role of phosphoinositide 3‐kinase and phosphatidic acid in the regulation of mammalian target of rapamycin following eccentric contractions , 2009, The Journal of physiology.

[72]  Steven K Boyd,et al.  Postpubertal Architectural Developmental Patterns Differ Between the L3 Vertebra and Proximal Tibia in Three Inbred Strains of Mice , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[73]  Ralph Müller,et al.  A novel in vivo mouse model for mechanically stimulated bone adaptation – a combined experimental and computational validation study , 2008, Computer methods in biomechanics and biomedical engineering.

[74]  Steven K Boyd,et al.  Radiation effects on bone architecture in mice and rats resulting from in vivo micro-computed tomography scanning. , 2008, Medical engineering & physics.

[75]  M. Drummond,et al.  Leucine-enriched nutrients and the regulation of mammalian target of rapamycin signalling and human skeletal muscle protein synthesis , 2008, Current opinion in clinical nutrition and metabolic care.

[76]  Shibing Yu,et al.  Rapamycin inhibits osteoblast proliferation and differentiation in MC3T3‐E1 cells and primary mouse bone marrow stromal cells , 2008, Journal of cellular biochemistry.

[77]  J. Prieto,et al.  Reactive oxygen species (ROS) mediate the effects of leucine on translation regulation and type I collagen production in hepatic stellate cells. , 2007, Biochimica et biophysica acta.

[78]  Ralph Müller,et al.  Automated compartmental analysis for high-throughput skeletal phenotyping in femora of genetic mouse models. , 2007, Bone.

[79]  Mary L Bouxsein,et al.  Age‐Related Changes in Trabecular Architecture Differ in Female and Male C57BL/6J Mice , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[80]  D. Chinkes,et al.  Aging does not impair the anabolic response to a protein-rich meal. , 2007, The American journal of clinical nutrition.

[81]  A. Mitnitski,et al.  Frailty in relation to the accumulation of deficits. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[82]  S. Chien,et al.  Regulation of mTOR by Mechanically Induced Signaling Events in Skeletal Muscle , 2006, Cell cycle.

[83]  R. Wolfe,et al.  Aging is associated with diminished accretion of muscle proteins after the ingestion of a small bolus of essential amino acids. , 2005, The American journal of clinical nutrition.

[84]  T. D. Pugh,et al.  Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging , 2005, Science.

[85]  J. Babraj,et al.  Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[86]  Kenneth Rockwood,et al.  Operationalizing a Frailty Index from a Standardized Comprehensive Geriatric Assessment , 2004, Journal of the American Geriatrics Society.

[87]  P. Gachon,et al.  Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[88]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[89]  P. Gallagher,et al.  Mitogen‐activated protein kinase (MAPK) pathway activation: effects of age and acute exercise on human skeletal muscle , 2003, The Journal of physiology.

[90]  J. Gasser.  Assessing bone quantity by pQCT. , 1995, Bone.

[91]  M. Holick,et al.  Differentiating between orchiectomized rats and controls using measurements of trabecular bone density: A comparison among DXA, Histomorphometry, and peripheral quantitative computerized tomography , 1995, Calcified Tissue International.

[92]  J. Compston,et al.  Combined inter-observer and inter-method variation in bone histomorphometry. , 1992, Bone.

[93]  M. Drezner,et al.  Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[94]  R. Erben,et al.  Histomorphometry in Rodents. , 2019, Methods in molecular biology.

[95]  Feodor Price,et al.  Satellite cells and the muscle stem cell niche. , 2013, Physiological reviews.

[96]  Kenneth Rockwood,et al.  Searching for an operational definition of frailty: a Delphi method based consensus statement: the frailty operative definition-consensus conference project. , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[97]  R. Erben,et al.  Histomorphometry in rodents. , 2012, Methods in molecular biology.

[98]  S. Xuan,et al.  Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells , 2012 .

[99]  F. Lambers.  Functional bone imaging in an in vivo mouse model of bone adaptation, aging and disease , 2011 .

[100]  W. Weber,et al.  Anesthesia and other considerations for in vivo imaging of small animals. , 2008, ILAR journal.

[101]  K. Meijer,et al.  Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly. , 2007, American journal of physiology. Endocrinology and metabolism.

[102]  P. Rüegsegger,et al.  A microtomographic system for the nondestructive evaluation of bone architecture , 2006, Calcified Tissue International.

[103]  J. Compston,et al.  Interobserver variation in bone histomorphometry , 1986 .