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Browsing by Author "Reyes Fernandez, Perla C."
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Item Effects of Dietary Protein Source and Quantity on Bone Morphology and Body Composition Following a High-Protein Weight-Loss Diet in a Rat Model for Postmenopausal Obesity(MDPI, 2022-05-28) Wright, Christian S.; Hill, Erica R.; Reyes Fernandez, Perla C.; Thompson, William R.; Gallant, Maxime A.; Campbell, Wayne W.; Main, Russell P.; Physical Therapy, School of Health and Human SciencesHigher protein (>30% of total energy, HP)-energy restriction (HP-ER) diets are an effective means to improve body composition and metabolic health. However, weight loss (WL) is associated with bone loss, and the impact of HP-ER diets on bone is mixed and controversial. Recent evidence suggests conflicting outcomes may stem from differences in age, hormonal status, and the predominant source of dietary protein consumed. Therefore, this study investigated the effect of four 12-week energy restriction (ER) diets varying in predominate protein source (beef, milk, soy, casein) and protein quantity (normal protein, NP 15% vs. high, 35%) on bone and body composition outcomes in 32-week-old obese, ovariectomized female rats. Overall, ER decreased body weight, bone quantity (aBMD, aBMC), bone microarchitecture, and body composition parameters. WL was greater with the NP vs. HP-beef and HP-soy diets, and muscle area decreased only with the NP diet. The HP-beef diet exacerbated WL-induced bone loss (increased trabecular separation and endocortical bone formation rates, lower bone retention and trabecular BMC, and more rod-like trabeculae) compared to the HP-soy diet. The HP-milk diet did not augment WL-induced bone loss. Results suggest that specific protein source recommendations may be needed to attenuate the adverse alterations in bone quality following an HP-ER diet in a model of postmenopausal obesity.Item Effects of Gabapentin and Pregabalin on Calcium Homeostasis: Implications for Physical Rehabilitation of Musculoskeletal Tissues(Springer, 2022) Reyes Fernandez, Perla C.; Wright, Christian S.; Warden, Stuart J.; Hum, Julia; Farach-Carson, Mary C.; Thompson, William R.; Physical Therapy, School of Health and Human SciencesPurpose of review: In this review, we discuss the mechanism of action of gabapentinoids and the potential consequences of long-term treatment with these drugs on the musculoskeletal system. Recent findings: Gabapentinoids, such as gabapentin (GBP) and pregabalin (PGB) were designed as antiepileptic reagents and are now commonly used as first-line treatment for neuropathic pain and increasingly prescribed off-label for other pain disorders such as migraines and back pain. GBP and PGB exert their analgesic actions by selectively binding the α2δ1 auxiliary subunit of voltage-sensitive calcium channels, thereby inhibiting channel function. Numerous tissues express the α2δ1 subunit where GBP and PGB can alter calcium-mediated signaling events. In tissues such as bone, muscle, and cartilage, α2δ1 has important roles in skeletal formation, mechanosensation, and normal tissue function/repair that may be affected by chronic use of gabapentinoids. Long-term use of gabapentinoids is associated with detrimental musculoskeletal outcomes, including increased fracture risk. Therefore, understanding potential complications is essential for clinicians to guide appropriate treatments.Item Gabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation(MDPI, 2022-12-12) Reyes Fernandez, Perla C.; Wright, Christian S.; Masterson, Adrianna N.; Yi, Xin; Tellman, Tristen V.; Bonteanu, Andrei; Rust, Katie; Noonan, Megan L.; White, Kenneth E.; Lewis, Karl J.; Sankar, Uma; Hum, Julia M.; Bix, Gregory; Wu, Danielle; Robling, Alexander G.; Sardar, Rajesh; Farach-Carson, Mary C.; Thompson, William R.; Physical Therapy, School of Health and Human SciencesOur understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified "tethering elements" (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α2δ1 and PLN domains and demonstrated for the first time that α2δ1 strongly associates with PLN via its domain III. Furthermore, α2δ1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α2δ1 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α2δ1, necessary for bone force transmission and sensitive to the drug GBP.Item Loss of the auxiliary α2δ1 voltage-sensitive calcium channel subunit impairs bone formation and anabolic responses to mechanical loading(Oxford University Press, 2024-01-10) Kelly, Madison M.; Sharma, Karan; Wright, Christian S.; Yi, Xin; Reyes Fernandez, Perla C.; Gegg, Aaron T.; Gorrell, Taylor A.; Noonan, Megan L.; Baghdady, Ahmed; Sieger, Jacob A.; Dolphin, Annette C.; Warden, Stuart J.; Deosthale, Padmini; Plotkin, Lilian I.; Sankar, Uma; Hum, Julia M.; Robling, Alexander G.; Farach-Carson, Mary C.; Thompson, William R.; Physical Therapy, School of Health and Human SciencesVoltage-sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α1) subunit of VSCCs allows Ca2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α2δ1 subunit influences gating kinetics of the α1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α2δ1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1, the gene encoding α2δ1. Dual-energy X-ray absorptiometry and microcomputed tomography imaging demonstrated that deletion of α2δ1 diminished bone mineral content and density in both male and female C57BL/6 mice. Structural differences manifested in both trabecular and cortical bone for males, while the absence of α2δ1 affected only cortical bone in female mice. Deletion of α2δ1 impaired skeletal mechanical properties in both sexes, as measured by three-point bending to failure. While no changes in osteoblast number or activity were found for either sex, male mice displayed a significant increase in osteoclast number, accompanied by increased eroded bone surface and upregulation of genes that regulate osteoclast differentiation. Deletion of α2δ1 also rendered the skeleton insensitive to exogenous mechanical loading in males. While previous work demonstrates that VSCCs are essential for anabolic responses to mechanical loading, the mechanism by which these channels sense and respond to force remained unclear. Our data demonstrate that the α2δ1 auxiliary VSCC subunit functions to maintain baseline bone mass and strength through regulation of osteoclast activity and also provides skeletal mechanotransduction in male mice. These data reveal a molecular player in our understanding of the mechanisms by which VSCCs influence skeletal adaptation.