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Targeting mitochondrial dysfunction using methylene blue or mitoquinone to improve skeletal aging

Poudel, Sher Bahadur; Frikha-Benayed, Dorra; Ruff, Ryan R; Yildirim, Gozde; Dixit, Manisha; Korstanje, Ron; Robinson, Laura; Miller, Richard A; Harrison, David E; Strong, John R; Schaffler, Mitchell B; Yakar, Shoshana
Methylene blue (MB) is a well-established antioxidant that has been shown to improve mitochondrial function in both in vitro and in vivo settings. Mitoquinone (MitoQ) is a selective antioxidant that specifically targets mitochondria and effectively reduces the accumulation of reactive oxygen species. To investigate the effect of long-term administration of MB on skeletal morphology, we administered MB to aged (18 months old) female C57BL/J6 mice, as well as to adult male and female mice with a genetically diverse background (UM-HET3). Additionally, we used MitoQ as an alternative approach to target mitochondrial oxidative stress during aging in adult female and male UM-HET3 mice. Although we observed some beneficial effects of MB and MitoQ in vitro, the administration of these compounds in vivo did not alter the progression of age-induced bone loss. Specifically, treating 18-month-old female mice with MB for 6 or 12 months did not have an effect on age-related bone loss. Similarly, long-term treatment with MB from 7 to 22 months or with MitoQ from 4 to 22 months of age did not affect the morphology of cortical bone at the mid-diaphysis of the femur, trabecular bone at the distal-metaphysis of the femur, or trabecular bone at the lumbar vertebra-5 in UM-HET3 mice. Based on our findings, it appears that long-term treatment with MB or MitoQ alone, as a means to reduce skeletal oxidative stress, is insufficient to inhibit age-associated bone loss. This supports the notion that interventions solely with antioxidants may not provide adequate protection against skeletal aging.
PMID: 38535998
ISSN: 1945-4589
CID: 5645472

Excess Growth Hormone Triggers Inflammation-Associated Arthropathy, Subchondral Bone Loss, and Arthralgia

Poudel, Sher Bahadur; Ruff, Ryan R; Yildirim, Gozde; Dixit, Manisha; Michot, Benoit; Gibbs, Jennifer L; Ortiz, Silvana Duran; Kopchick, John J; Kirsch, Thorsten; Yakar, Shoshana
Growth hormone (GH) is a key mediator of skeletal growth. In humans, excess GH secretion due to pituitary adenoma, seen in patients with acromegaly, results in severe arthropathies. This study investigated the effects of long-term excess GH on the knee joint tissues. One year-old wild-type (WT) and bovine GH (bGH) transgenic mice were used as a model for excess GH. bGH mice showed increased sensitivity to mechanical and thermal stimuli, compared with WT mice. Micro-computed tomography analyses of the distal femur subchondral bone revealed significant reductions in trabecular thickness and significantly reduced bone mineral density of the tibial subchondral bone-plate that were associated with increased osteoclast activity in both male and female bGH compared with WT mice. bGH mice showed severe loss of matrix from the articular cartilage, osteophytosis, synovitis, and ectopic chondrogenesis. Articular cartilage loss in the bGH mice was associated with elevated markers of inflammation and chondrocyte hypertrophy. Finally, hyperplasia of synovial cells was associated with increased expression of Ki-67 and diminished p53 levels in the synovium of bGH mice. Unlike the low-grade inflammation seen in primary osteoarthritis, arthropathy caused by excess GH affects all joint tissues and triggers severe inflammatory response. Data of this study suggest that treatment of acromegalic arthropathy should involve inhibition of ectopic chondrogenesis and chondrocyte hypertrophy.
PMID: 36870529
ISSN: 1525-2191
CID: 5435002

Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice

Yildirim, Gozde; Bergamo, Edmara T P; Poudel, Sher Bahadur; Ruff, Ryan R; Dixit, Manisha; Hu, Bin; Mijares, Dindo Q; Witek, Lukasz; Chlebek, Carolyn; Harrison, David E; Strong, Randy; Miller, Richard A; Ladiges, Warren; Bromage, Timothy G; Rosen, Clifford J; Yakar, Shoshana
Sodium glucose cotransporter-2 inhibitors (SGLT2is) promote urinary glucose excretion and decrease plasma glucose levels independent of insulin. Canagliflozin (CANA) is an SGLT2i, which is widely prescribed, to reduce cardiovascular complications, and as a second-line therapy after metformin in the treatment of type 2 diabetes mellitus. Despite the robust metabolic benefits, reductions in bone mineral density (BMD) and cortical fractures were reported for CANA-treated subjects. In collaboration with the National Institute on Aging (NIA)-sponsored Interventions Testing Program (ITP), we tested skeletal integrity of UM-HET3 mice fed control (137 mice) or CANA-containing diet (180 ppm, 156 mice) from 7 to 22 months of age. Micro-computed tomography (micro-CT) revealed that CANA treatment caused significant thinning of the femur mid-diaphyseal cortex in both male and female mice, did not affect trabecular bone architecture in the distal femur or the lumbar vertebra-5 in male mice, but was associated with thinning of the trabeculae at the distal femur in CANA-treated female mice. In male mice, CANA treatment is associated with significant reductions in cortical bone volumetric BMD by micro-CT, and by quantitative backscattered scanning electron microscopy. Raman microspectroscopy, taken at the femur mid-diaphyseal posterior cortex, showed significant reductions in the mineral/matrix ratio and an increased carbonate/phosphate ratio in CANA-treated male mice. These data were supported by thermogravimetric assay (TGA) showing significantly decreased mineral and increased carbonate content in CANA-treated male mice. Finally, the sintered remains of TGA were subjected to X-ray diffraction and showed significantly higher fraction of whitlockite, a calcium orthophosphate mineral, which has higher resorbability than hydroxyapatite. Overall, long-term CANA treatment compromised bone morphology and mineral composition of bones, which likely contribute to increased fracture risk seen with this drug.
PMID: 37166526
ISSN: 2509-2723
CID: 5495712

Lifelong Excess in GH Elicits Sexually Dimorphic Effects on Skeletal Morphology and Bone Mechanical Properties

Dixit, Manisha; Louis, Leeann D; Basta-Pljakic, Jelena; Yildirim, Gozde; Poudel, Sher-Bahadur; Kumararaja, Fancy; List, Edward O; Duran, Silvana Ortiz; Kopchick, John J; Ruff, Ryan R; Schaffler, Mitchell B; Yakar, Shoshana
Excess in growth hormone (GH) levels, seen in patients with acromegaly, is associated with increases in fractures. This happens despite wider bones and independent of bone mineral density. We used the bovine GH (bGH) transgenic mice, which show constitutive excess in GH and insulin-like growth factor 1 (IGF-1) in serum and tissues, to study how lifelong increases in GH and IGF-1 affect skeletal integrity. Additionally, we crossed the acid labile subunit (ALS) null (ALSKO) to the bGH mice to reduce serum IGF-1 levels. Our findings indicate sexually dimorphic effects of GH on cortical and trabecular bone. Male bGH mice showed enlarged cortical diameters, but with marrow cavity expansion and thin cortices as well as increased vascular porosity that were associated with reductions in diaphyseal strength and stiffness. In contrast, female bGH mice presented with significantly smaller-diameter diaphysis, with greater cortical bone thickness and with a slightly reduced tissue elastic modulus (by microindentation), ultimately resulting in overall stronger, stiffer bones. We found increases in C-terminal telopeptide of type 1 collagen and procollagen type 1 N propeptide in serum, independent of circulating IGF-1 levels, indicating increased bone remodeling with excess GH. Sexual dimorphism in response to excess GH was also observed in the trabecular bone compartment, particularly at the femur distal metaphysis. Female bGH mice preserved their trabecular architecture during aging, whereas trabecular bone volume in male bGH mice significantly reduced and was associated with thinning of the trabeculae. We conclude that pathological excess in GH results in sexually dimorphic changes in bone architecture and gains in bone mass that affect whole-bone mechanical properties, as well as sex-specific differences in bone material properties. © 2022 American Society for Bone and Mineral Research (ASBMR).
PMID: 36069368
ISSN: 1523-4681
CID: 5332432

Fsp27 plays a crucial role in muscle performance

Slayton, Mark; Balakrishnan, Bijinu; Gupta, Abhishek; Jobe, Scott; Puri, Ishika; Neely, Savannah; Tamori, Yoshikazu; Russ, David W; Yildrim, Gozde; Yakar, Shoshana; Sharma, Vishva M; Puri, Vishwajeet
Fsp27 was previously identified as a lipid droplet-associated protein in adipocytes. Various studies have shown that it plays a role in the regulation of lipid homeostasis in adipose tissue and liver. However, its function in muscle, which also accumulate and metabolize fat, remains completely unknown. Our present study identifies a novel role of Fsp27 in muscle performance. Here we demonstrate that Fsp27-/- and Fsp27+/- mice, both males and females, had severely impaired muscle endurance and exercise capacity compared to wild-type controls. Liver and muscle glycogen stores were similar amongst all groups fed or fasted, and before or after exercise. Reduced muscle performance in Fsp27-/- and Fsp27+/- mice was associated with severely decreased fat content in the muscle. Furthermore, results in heterozygous Fsp27+/- mice indicate that Fsp27 haploinsufficiency undermines muscle performance in both males and females. In sum, our physiological findings reveal that Fsp27 plays a critical role in muscular fat storage, muscle endurance, and muscle strength.
PMID: 35157807
ISSN: 1522-1555
CID: 5171602


Dixit, M.; Fujimoto, M.; Maystadt, I.; Dauber, A.; Rauch, A.; Schepper, J. D.; Yildirim, G.; Zhang, Y.; Hwa, V.; Yakar, S.
ISSN: 0937-941x
CID: 5208012

Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

Barrios, Vicente; Chowen, Julie A; Martín-Rivada, Álvaro; Guerra-Cantera, Santiago; Pozo, Jesús; Yakar, Shoshana; Rosenfeld, Ron G; Pérez-Jurado, Luis A; Suárez, Juan; Argente, Jesús
The growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.
PMID: 34944082
ISSN: 2073-4409
CID: 5107592

Induction of somatopause in adult mice compromises bone morphology and exacerbates bone loss during aging

Dixit, Manisha; Duran-Ortiz, Silvana; Yildirim, Godze; Poudel, Sher Bahadur; Louis, Leeann D; Bartke, Andrzej; Schaffler, Mitchell B; Kopchick, John J; Yakar, Shoshana
Somatopause refers to the gradual declines in growth hormone (GH) and insulin-like growth factor-1 throughout aging. To define how induced somatopause affects skeletal integrity, we used an inducible GH receptor knockout (iGHRKO) mouse model. Somatopause, induced globally at 6 months of age, resulted in significantly more slender bones in both male and female iGHRKO mice. In males, induced somatopause was associated with progressive expansion of the marrow cavity leading to significant thinning of the cortices, which compromised bone strength. We report progressive declines in osteocyte lacunar number, and increases in lacunar volume, in iGHRKO males, and reductions in lacunar number accompanied by ~20% loss of overall canalicular connectivity in iGHRKO females by 30 months of age. Induced somatopause did not affect mineral/matrix ratio assessed by Raman microspectroscopy. We f ound significant increases in bone marrow adiposity and high levels of sclerostin, a negative regulator of bone formation in iGHRKO mice. Surprisingly, however, despite compromised bone morphology, osteocyte senescence was reduced in the iGHRKO mice. In this study, we avoided the confounded effects of constitutive deficiency in the GH/IGF-1 axis on the skeleton during growth, and specifically dissected its effects on the aging skeleton. We show here, for the first time, that induced somatopause compromises bone morphology and the bone marrow environment.
PMID: 34811875
ISSN: 1474-9726
CID: 5064002

Growth hormone receptor gene disruption in mature-adult mice improves male insulin sensitivity and extends female lifespan

Duran-Ortiz, Silvana; List, Edward O; Ikeno, Yuji; Young, Jonathan; Basu, Reetobrata; Bell, Stephen; McHugh, Todd; Funk, Kevin; Mathes, Samuel; Qian, Yanrong; Kulkarni, Prateek; Yakar, Shoshana; Berryman, Darlene E; Kopchick, John J
Studies in multiple species indicate that reducing growth hormone (GH) action enhances healthy lifespan. In fact, GH receptor knockout (GHRKO) mice hold the Methuselah prize for the world's longest-lived laboratory mouse. We previously demonstrated that GHR ablation starting at puberty (1.5 months), improved insulin sensitivity and female lifespan but results in markedly reduced body size. In this study, we investigated the effects of GHR disruption in mature-adult mice at 6 months old (6mGHRKO). These mice exhibited GH resistance (reduced IGF-1 and elevated GH serum levels), increased body adiposity, reduced lean mass, and minimal effects on body length. Importantly, 6mGHRKO males have enhanced insulin sensitivity and reduced neoplasms while females exhibited increased median and maximal lifespan. Furthermore, fasting glucose and oxidative damage was reduced in females compared to males irrespective of Ghr deletion. Overall, disrupted GH action in adult mice resulted in sexual dimorphic effects suggesting that GH reduction at older ages may have gerotherapeutic effects.
PMID: 34811874
ISSN: 1474-9726
CID: 5063992

Sexual dimorphic impact of adult-onset somatopause on life span and age-induced osteoarthritis

Poudel, Sher Bahadur; Dixit, Manisha; Yildirim, Gozde; Cordoba-Chacon, Jose; Gahete, Manuel D; Yuji, Ikeno; Kirsch, Thorsten; Kineman, Rhonda D; Yakar, Shoshana
Osteoarthritis (OA), the most prevalent joint disease, is a major cause of disability worldwide. Growth hormone (GH) has been suggested to play significant roles in maintaining articular chondrocyte function and ultimately articular cartilage (AC) homeostasis. In humans, the age-associated decline in GH levels was hypothesized to play a role in the etiology of OA. We studied the impact of adult-onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity including the AC, in 23- to 30-month-old male and female mice on C57/BL6 genetic background. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end-of-life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice, evidenced by AC degradation in both femur and tibia, and significantly increased osteophyte formation in AOiGHD females. AOiGHD males showed significant increases in the thickness of the synovial lining cell layer that was associated with increased markers of inflammation (IL-6, iNOS). Furthermore, male AOiGHD showed significant increases in matrix metalloproteinase-13 (MMP-13), p16, and β-galactosidase immunoreactivity in the AC as compared to controls, indicating increased cell senescence. In conclusion, while the life span of AOiGHD females increased, their health span was compromised by high-grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity.
PMID: 34240807
ISSN: 1474-9726
CID: 4933602