Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice.
Li Hongshuai,Sun Hui,Qian Baoli,Feng Wei,Carney Dwayne,Miller Jennifer,Hogan MaCalus V,Wang Ling
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy seen in children. In addition to skeletal muscle, DMD also has a significant impact on bone. The pathogenesis of bone abnormalities in DMD is still unknown. Recently, we have identified a novel bone-regulating cytokine, fibroblast growth factor-21 (FGF-21), which is dramatically upregulated in skeletal muscles from DMD animal models. We hypothesize that muscle-derived FGF-21 negatively affects bone homeostasis in DMD. Dystrophin/utrophin double-knockout (dKO) mice were used in this study. We found that the levels of circulating FGF-21 were significantly higher in dKO mice than in age-matched WT controls. Further tests on FGF-21 expressing tissues revealed that both FGF-21 mRNA and protein expression were dramatically upregulated in dystrophic skeletal muscles, whereas FGF-21 mRNA expression was downregulated in liver and white adipose tissue (WAT) compared to WT controls. Neutralization of circulating FGF-21 by i.p. injection of anti-FGF-21 antibody significantly alleviated progressive bone loss in weight-bearing (vertebra, femur, and tibia) and non-weight bearing bones (parietal bones) in dKO mice. We also found that FGF-21 directly promoted RANKL-induced osteoclastogenesis from bone marrow macrophages (BMMs), as well as promoted adipogenesis while concomitantly inhibiting osteogenesis of bone marrow mesenchymal stem cells (BMMSCs). Furthermore, fibroblast growth factor receptors (FGFRs) and co-receptor β-klotho (KLB) were expressed in bone cells (BMM-derived osteoclasts and BMMSCs) and bone tissues. KLB knockdown by small interfering RNAs (siRNAs) significantly inhibited the effects of FGF21 on osteoclast formation of BMMs and on adipogenic differentiation of BMMSCs, indicating that FGF-21 may directly affect dystrophic bone via the FGFRs-β-klotho complex. In conclusion, this study shows that dystrophic skeletal muscles express and secrete significant levels of FGF-21, which negatively regulates bone homeostasis and represents an important pathological factor for the development of bone abnormalities in DMD. The current study highlights the importance of muscle/bone cross-talk via muscle-derived factors (myokines) in the pathogenesis of bone abnormalities in DMD. © 2019 American Society for Bone and Mineral Research.
Low Plasma Klotho Concentrations and Decline of Knee Strength in Older Adults.
Semba Richard D,Ferrucci Luigi,Sun Kai,Simonsick Eleanor,Turner Randi,Miljkovic Iva,Harris Tamara,Schwartz Ann V,Asao Keiko,Kritchevsky Stephen,Newman Anne B,
The journals of gerontology. Series A, Biological sciences and medical sciences
BACKGROUND:Although the "anti-aging hormone" klotho is associated with sarcopenia in mice, the relationship between klotho and muscle strength in older adults is not well known. METHODS:Plasma klotho concentrations were measured in 2,734 older adults, aged 71-80 years, who participated in the Health, Aging and Body Composition Study, a prospective observational cohort study conducted in Memphis, TN and Pittsburgh, PA. Knee extension strength was measured using isokinetic dynamometry at baseline and follow-up 2 and 4 years later. Knee extension strength was normalized for weight. RESULTS:At baseline, participants in the highest tertile of plasma klotho had higher knee extension strength (β = .72, standard error [SE] = .018, p < .0001) compared with those in the lowest tertile in a multivariable linear regression model adjusting for age, sex, race, smoking, study site, C-reactive protein, interleukin-6, and diabetes. Participants in the highest tertile of plasma klotho at baseline had less of a decline in knee strength over 4 years of follow-up (β = -.025, SE = .011, p = .02) compared with those in the lowest tertile in a multivariable linear regression model adjusting for the same covariates above. CONCLUSIONS:Plasma klotho concentrations were an independent predictor of changes in knee strength over time in older adults. Further studies are needed to identify the biological mechanisms by which circulating klotho could modify skeletal muscle strength.
Association of Serum Klotho with Loss of Bone Mineral Density and Fracture Risk in Older Adults.
Chalhoub Didier,Marques Elisa,Meirelles Osorio,Semba Richard D,Ferrucci Luigi,Satterfield Suzanne,Nevitt Michael,Cauley Jane A,Harris Tamara,
Journal of the American Geriatrics Society
OBJECTIVES:Klotho deficiency has been previously linked to aging-like phenotypes such as osteoporosis, cognitive impairment, and sarcopenia. Low serum klotho was shown to be related to grip strength and disability. Nonetheless, no previous study has explored the association between serum klotho and fractures. The purpose of this report is to examine the relationship of serum klotho with bone mineral density (BMD) loss and fractures in older adults. DESIGN:The Health, Aging, and Body Composition (Health ABC) Study is a longitudinal cohort study of 3,075 community-dwelling older adults. SETTING:US clinical centers. PARTICIPANTS:Two thousand seven hundred and seventy six well-functioning black and white adults aged 70 to 79 years with serum klotho measurements were followed up for a median of 5 years. MEASUREMENTS:Percent annualized BMD change and fracture risk were compared across klotho quartiles. A Poisson distribution was used to calculate age-adjusted fracture incidence rates, and Cox proportional hazards models for multivariable-adjusted hazard ratios. RESULTS:The annualized percent changes in hip, femoral neck, and vertebral BMD were similar across klotho quartiles. Participants experienced 507 nonspine fractures, 203 hip fractures, and 135 vertebral fractures. The Incidence rate (IR) of nonspine fractures was 17 per 1,000 person-years. The most frequent site was hip (IR = 6 per 1,000 person-years) and the IR of vertebral fractures was 3 per 1,000 person-years. There was no association between the lowest quartile of plasma klotho and nonspine (hazard ratio (HR) = 1.19, 95% confidence interval (CI) = 0.86-1.65), hip (HR = 1.34, 95% CI = 0.79-2.27), or vertebral fractures (HR = 1.17, 95% CI = 0.65-2.11). CONCLUSION:Although klotho gene is a susceptible gene for reduced BMD, klotho blood concentration does not appear to be a predictor of bone loss or fracture risk in well-functioning older adults.
Physical performance, plasma S-klotho, and all-cause mortality in elderly dialysis patients: A prospective cohort study.
Valenzuela Pedro L,Cobo Fernando,Diez-Vega Ignacio,Sánchez-Hernández Rosa,Pedrero-Chamizo Raquel,Verde-Rello Zoraida,González-Gross Marcela,Santiago Catalina,Pérez Ruiz Margarita
The secreted protein form of the α-klotho gene, S-klotho, is gaining popularity as a predictor of overall morbimortality, and its role in dialysis patients has been recently highlighted. However, physical performance -which can be assessed through practical field-tests- might be a more practical prognostic marker. The present study aimed to analyze the relationship between physical performance, plasma S-klotho and all-cause mortality in this population. 30 male hemodialysis patients (71 ± 9 years) participated in this prospective, cohort study. Their plasma S-klotho levels and physical performance (assessed by means of the 6-minute walk test [6MWT], handgrip strength, and the sit-to-stand test [STS]) were determined at baseline, and the incidence of mortality was assessed 18-month later. Lower S-klotho levels were associated with a worse performance in all physical tests (all p < 0.05). 12 participants died during the 18 months following baseline measurements. An increased mortality risk was observed in those patients with a worse performance in the STS (RR: 3.0 [95%CI: 1.01-8.95], p < 0.05), the handgrip test (RR: 3.0 [95%CI: 1.01-8.95], p < 0.05) and the 6MWT (RR: 5.0 [95%CI: 1.31-19.07], p < 0.01), being the latter the best predictor of mortality. By contrast, this relationship was not found for plasma S-klotho (RR: 1.6 [95%CI: 0.65-1.35], p > 0.05). In summary, low plasma S-klotho levels are related to impaired physical performance in male dialysis patients. However, physical performance appears as a better and more practical predictor of mortality in this patient population.
Frailty and sarcopenia as the basis for the phenotypic manifestation of chronic diseases in older adults.
Angulo Javier,El Assar Mariam,Rodríguez-Mañas Leocadio
Molecular aspects of medicine
Frailty is a functional status that precedes disability and is characterized by decreased functional reserve and increased vulnerability. In addition to disability, the frailty phenotype predicts falls, institutionalization, hospitalization and mortality. Frailty is the consequence of the interaction between the aging process and some chronic diseases and conditions that compromise functional systems and finally produce sarcopenia. Many of the clinical manifestations of frailty are explained by sarcopenia which is closely related to poor physical performance. Reduced regenerative capacity, malperfusion, oxidative stress, mitochondrial dysfunction and inflammation compose the sarcopenic skeletal muscle alterations associated to the frailty phenotype. Inflammation appears as a common determinant for chronic diseases, sarcopenia and frailty. The strategies to prevent the frailty phenotype include an adequate amount of physical activity and exercise as well as pharmacological interventions such as myostatin inhibitors and specific androgen receptor modulators. Cell response to stress pathways such as Nrf2, sirtuins and klotho could be considered as future therapeutic interventions for the management of frailty phenotype and aging-related chronic diseases.
Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study.
Semba Richard D,Cappola Anne R,Sun Kai,Bandinelli Stefania,Dalal Mansi,Crasto Candace,Guralnik Jack M,Ferrucci Luigi
European journal of applied physiology
Handgrip strength is a strong indicator of total body muscle strength and is a predictor of poor outcomes in older adults. The aging suppressor gene klotho encodes a single-pass transmembrane protein that is secreted as a circulating hormone. In mice, disruption of klotho expression results in a syndrome that includes sarcopenia, atherosclerosis, osteoporosis, and shortened lifespan, and conversely, overexpression of klotho leads to a greater longevity. The objective was to determine whether plasma klotho levels are related to skeletal muscle strength in humans. We measured plasma klotho in 804 adults, ≥65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. Grip strength was positively correlated with plasma klotho at threshold <681 pg/mL. After adjusting for age, sex, education, smoking, physical activity, cognition, and chronic diseases, plasma klotho (per 1 standard deviation increase) was associated with grip strength (beta = 1.20, standard error = 0.35, P = 0.0009) in adults with plasma klotho <681 pg/mL. These results suggest that older adults with lower plasma klotho have poor skeletal muscle strength.