Skeletal Integrity Research Articles

Navigating Post-Traumatic Osteoporosis: A Comprehensive Review of Epidemiology, Pathophysiology, Diagnosis, Treatment, and Future Directions.

Post-traumatic osteoporosis (PTO) presents a significant challenge in clinical practice, characterized by demineralization and decreased skeletal integrity following severe traumatic injuries. This literature review manuscript addresses the knowledge gaps surrounding PTO, encompassing its epidemiology, pathophysiology, risk factors, diagnosis, treatment, prognosis, and future directions. This review emphasizes the complexity of the etiology of PTO, highlighting the dysregulation of biomineralization processes, inflammatory cytokine involvement, hormonal imbalances, glucocorticoid effects, vitamin D deficiency, and disuse osteoporosis. Moreover, it underscores the importance of multidisciplinary approaches for risk mitigation and advocates for improved diagnostic strategies to differentiate PTO from other musculoskeletal pathologies. This manuscript discusses various treatment modalities, including pharmacotherapy, dietary management, and physical rehabilitation, while also acknowledging the limited evidence on their long-term effectiveness and outcomes in PTO patients. Future directions in research are outlined, emphasizing the need for a deeper understanding of the molecular mechanisms underlying PTO and the evaluation of treatment strategies' efficacy. Overall, this review provides a comprehensive overview of PTO and highlights avenues for future investigation to enhance clinical management and patient outcomes.

The interaction between gut microbiome and bone health.

This review critically examines interconnected health domains like gut microbiome, bone health, interleukins, chronic periodontitis, and coronavirus disease 2019 (COVID-19), offering insights into fundamental mechanisms and clinical implications, contributing significantly to healthcare and biomedical research. This review explores the relationship between gut microbiome and bone health, a growing area of study. It provides insights into skeletal integrity and potential therapeutic avenues. The review also examines interleukins, chronic periodontitis, and COVID-19, highlighting the complexity of viral susceptibility and immune responses. It highlights the importance of understanding genetic predispositions and immune dynamics in the context of disease outcomes. The review emphasizes experimental evidence and therapeutic strategies, aligning with evidence-based medicine and personalized interventions. This approach offers actionable insights for healthcare practitioners and researchers, paving the way for targeted therapeutic approaches and improved patient outcomes. The implications of these findings for clinical practice and research underscore the importance of a multidisciplinary approach to healthcare that considers the complex interactions between genetics, immune responses, oral health, and systemic diseases. By leveraging advances in biomedical research, clinicians can optimize patient care and improve health outcomes across diverse patient populations.

Troponin T is elevated in a relevant proportion of patients with 5q-associated spinal muscular atrophy

Troponin T concentration (TNT) is commonly considered a marker of myocardial damage. However, elevated concentrations have been demonstrated in numerous neuromuscular disorders, pointing to the skeletal muscle as a possible extracardiac origin. The aim of this study was to determine disease-related changes of TNT in 5q-associated spinal muscular atrophy (SMA) and to screen for its biomarker potential in SMA. We therefore included 48 pediatric and 45 adult SMA patients in this retrospective cross-sequential observational study. Fluid muscle integrity and cardiac markers were analyzed in the serum of treatment-naïve patients and subsequently under disease-modifying therapies. We found a TNT elevation in 61% of SMA patients but no elevation of the cardiospecific isoform Troponin I (TNI). TNT elevation was more pronounced in children and particularly infants with aggressive phenotypes. In adults, TNT correlated to muscle destruction and decreased under therapy only in the subgroup with elevated TNT at baseline. In conclusion, TNT was elevated in a relevant proportion of patients with SMA with emphasis in infants and more aggressive phenotypes. Normal TNI levels support a likely extracardiac origin. Although its stand-alone biomarker potential seems to be limited, exploring TNT in SMA underlines the investigation of skeletal muscle integrity markers.

Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy

The effects of gender-affirming hormone therapy on the skeletal integrity and fracture risk in transitioning adolescent trans girls are unknown. To address this knowledge gap, we developed a mouse model to simulate male-to-female transition in human adolescents in whom puberty is first arrested by using gonadotrophin-releasing hormone analogs with subsequent estradiol treatment. Puberty was suppressed by orchidectomy in male mice at 5 weeks of age. At 3 weeks post-surgery, male-to-female mice were treated with a high dose of estradiol (~0.85 mg) by intraperitoneal silastic implantation for 12 weeks. Controls included intact and orchidectomized males at 3 weeks post-surgery, vehicle-treated intact males, intact females and orchidectomized males at 12 weeks post-treatment. Compared to male controls, orchidectomized males exhibited decreased peak bone mass accrual and a decreased maximal force the bone could withstand prior to fracture. Estradiol treatment in orchidectomized male-to-female mice compared to mice in all control groups was associated with an increased cortical thickness in the mid-diaphysis, while the periosteal circumference increased to a level that was intermediate between intact male and female controls, resulting in increased maximal force and stiffness. In trabecular bone, estradiol treatment increased newly formed trabeculae arising from the growth plate as well as mineralizing surface/bone surface and bone formation rate, consistent with the anabolic action of estradiol on osteoblast proliferation. These data support the concept that skeletal integrity can be preserved and that long-term fractures may be prevented in trans girls treated with GnRHa and a sufficiently high dose of GAHT. Further study is needed to identify an optimal dose of estradiol that protects the bone without adverse side effects.

Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function

Tauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.

The Integral Role of Magnesium in Muscle Integrity and Aging: A Comprehensive Review.

Aging is characterized by significant physiological changes, with the degree of decline varying significantly among individuals. The preservation of intrinsic capacity over the course of an individual's lifespan is fundamental for healthy aging. Locomotion, which entails the capacity for independent movement, is intricately connected with various dimensions of human life, including cognition, vitality, sensory perception, and psychological well-being. Notably, skeletal muscle functions as a pivotal nexus within this intricate framework. Any perturbation in its functionality can manifest as compromised physical performance and an elevated susceptibility to frailty. Magnesium is an essential mineral that plays a central role in approximately 800 biochemical reactions within the human body. Its distinctive physical and chemical attributes render it an indispensable stabilizing factor in the orchestration of diverse cellular reactions and organelle functions, thereby rendering it irreplaceable in processes directly impacting muscle health. This narrative review offers a comprehensive exploration of the pivotal role played by magnesium in maintaining skeletal muscle integrity, emphasizing the critical importance of maintaining optimal magnesium levels for promoting healthy aging.

DBC1maintains skeletal muscle integrity by enhancing myogenesis and preventing myofibre wasting.

Skeletal muscle atrophy, particularly ageing-related muscular atrophy such as sarcopenia, is a significant health concern. Despite its prevalence, the underlying mechanisms remain poorly understood, and specific approved medications are currently unavailable. Deleted in breast cancer 1 (DBC1) is a well-known regulator of senescence, metabolism or apoptosis. Recent reports suggest that DBC1 may also potentially regulate muscle function, as mice lacking DBC1 exhibit weakness and limpness. However, the function of DBC1 in skeletal muscle and its associated molecular mechanisms remain unknown, thus prompting the focus of this study. Tibialis anterior (TA) muscle-specific DBC1 knockdown C57BL/6J male mice were generated through a single injection of 2.00 E+11vg of adeno-associated virus 9 delivering single-guide RNA for DBC1. Grip strength and endurance were assessed 2months later, followed by skeletal muscle harvest. Muscle atrophy model was generated by cast immobilization of the mouse hindlimb for 2weeks. Molecular markers of atrophy were probed in muscles upon termination. Cardiotoxin (CTX) was injected in TA muscles of DBC1 knockdown mice, and muscle regeneration was assessed by immunohistochemistry, quantitative PCR and western blotting. DBC1 knockdown C2C12 cells and myotubes were investigated using immunofluorescence staining, Seahorse, immunohistology, fluorescence-activated cell sorting and RNA-sequencing analyses. DBC1 knockdown in skeletal muscle of young mice led to signatures of muscle atrophy, including a 28% reduction in muscle grip force (P=0.023), a 54.4% reduction in running distance (P=0.002), a 14.3% reduction in muscle mass (P=0.007) and significantly smaller myofibre cross-sectional areas (P<0.0001). DBC1 levels decrease in age-related or limb immobilization-induced atrophic mouse muscles and overexpress DBC1-attenuated atrophic phenotypes in these mice. Muscle regeneration was hampered in mice with CTX-induced muscle injury by DBC1 knockdown, as evidenced by reductions in myofibre cross-sectional areas of regenerating myofibres with centralized nuclei (P<0.0001), percentages of MyoG+ nuclei (P<0.0001) and fusion index (P<0.0001). DBC1 transcriptionally regulated mouse double minute 2 (MDM2), which mediated ubiquitination and degradation of forkhead box O3 (FOXO3). Increased FOXO3 proteins hampered myogenesis in DBC1 knockdown satellite cells by compromising around 50% of mitochondrial functions (P<0.001) and exacerbated atrophy in DBC1 knockdown myofibres by activating the ubiquitin-proteasome and autophagy-lysosome pathways. DBC1 is essential in maintaining skeletal muscle integrity by protecting against myofibres wasting and enhancing muscle regeneration via FOXO3. This research highlights the significance of DBC1 for healthy skeletal muscle function and its connection to muscular atrophy.

Circadian regulation of calcium and phosphorus homeostasis during the oviposition cycle in laying hens

Maintenance of calcium and phosphorus homeostasis in laying hens is crucial for preservation of skeletal integrity and eggshell quality, though physiological regulation of these systems is incompletely defined. To investigate changes in mineral and vitamin D3 homeostasis during the 24-h egg formation cycle, 32-wk-old commercial laying hens were sampled at 1, 3, 4, 6, 7, 8, 12, 15, 18, 21, 23, and 24 h post-oviposition (HPOP; n ≥ 4). Ovum location and egg calcification stage were recorded, and blood chemistry, plasma vitamin D3 metabolites, circulating parathyroid hormone (PTH), and expression of genes mediating uptake and utilization of calcium and phosphorus were evaluated. Elevated levels of renal 25-hydroxylase from 12 to 23 HPOP suggest this tissue might play a role in vitamin D3 25-hydroxylation during eggshell calcification. In shell gland, retinoid-x-receptor gamma upregulation between 6 and 8 HPOP followed by subsequently increased vitamin D receptor indicate that vitamin D3 signaling is important for eggshell calcification. Increased expression of PTH, calcitonin, and fibroblast growth factor 23 (FGF23) receptors in the shell gland between 18 and 24 HPOP suggest elevated sensitivity to these hormones toward the end of eggshell calcification. Shell gland sodium-calcium exchanger 1 was upregulated between 4 and 7 HPOP and plasma membrane calcium ATPase 1 increased throughout eggshell calcification, suggesting the primary calcium transporter may differ according to eggshell calcification stage. Expression in shell gland further indicated that bicarbonate synthesis precedes transport, where genes peaked at 6 to 7 and 12 to 18 HPOP, respectively. Inorganic phosphorus transporter 1 (PiT-1) expression peaked in kidney between 12 and 15 HPOP, likely to excrete excess circulating phosphorus, and in shell gland between 18 and 21 HPOP. Upregulation of FGF23 receptors and PiT-1 during late eggshell calcification suggest shell gland phosphorus uptake is important at this time. Together, these findings identified potentially novel hormonal pathways involved in calcium and phosphorus homeostasis along with associated circadian patterns in gene expression that can be used to devise strategies aimed at improving eggshell and skeletal strength in laying hens.

The unexpected role of lipid droplets in the regulation of muscle stem cells fate

Muscle stem cells (MuSCs) are skeletal muscle resident stem cells responsible of skeletal muscle regeneration and tissue integrity maintenance. It is now becoming prominent that the ability of MuSCs either to self-renew or differentiate is affected by cellular metabolism. Recently, a study elucidated that lipid droplets (LDs) are novel key regulators of MuSC fate. Indeed, LDs distribute differently depending on MuSC state during the regeneration process, as LDLow MuSCs are more proned to self-renew while LDHigh MuSCs commit to differentiation. Therefore, these findings highlight that the LD turnover is necessary for MuSC fate decision, opening the question of the molecular mechanism underlying lipid metabolism regulation of MuSC fate determination.

Microvascular Disease Associates with Larger Osteocyte Lacunae in Cortical Bone in Type 2 Diabetes Mellitus.

Clinical studies indicate that microvascular disease (MVD) affects bone microstructure and decreases bone strength in type 2 diabetes mellitus (T2D). Osteocytes are housed in small voids within the bone matrix and lacunae and act as sensors of mechanical forces in bone. These cells regulate osteoclastic bone resorption and osteoblastic bone formation as well as osteocytic perilacunar remodeling. We hypothesized that MVD changes morphometric osteocyte lacunar parameters in individuals with T2D. We collected iliac crest bone biopsies from 35 individuals (10 female, 25 male) with T2D with MVD (15%) or without MVD (21%) with a median age of 67 years (interquartile range [IQR] 62-72 years). The participants were included based on c-peptide levels >700 pmol L-1, absence of anti-GAD65 antibodies, and glycated hemoglobin (HbA1c) levels between 40 and 82 mmol mol-1 or 5.8% and 9.7%, respectively. We assessed osteocyte lacunar morphometric parameters in trabecular and cortical bone regions using micro-computed tomography (micro-CT) at a nominal resolution of 1.2 μm voxel size. The cortical osteocyte lacunar volume (Lc.V) was 7.7% larger (p = 0.05) and more spherical (Lc.Sr, p < 0.01) in the T2D + MVD group. Using linear regression, we found that lacunar density (Lc.N/BV) in trabecular but not cortical bone was associated with HbA1c (p < 0.05, R 2 = 0.067) independently of MVD. Furthermore, Lc.V was larger and Lc.Sr higher in the center than in the periphery of the trabecular and cortical bone regions (p < 0.05). In conclusion, these data imply that MVD may impair skeletal integrity, possibly contributing to increased skeletal fragility in T2D complicated by MVD. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The Role of Vitamin D in Skeletal Muscle Repair and Regeneration in Animal Models and Humans: A Systematic Review.

Vitamin D deficiency, prevalent worldwide, is linked to muscle weakness, sarcopenia, and falls. Muscle regeneration is a vital process that allows for skeletal muscle tissue maintenance and repair after injury. PubMed and Web of Science were used to search for studies published prior to May 2023. We assessed eligible studies that discussed the relationship between vitamin D, muscle regeneration in this review. Overall, the literature reports strong associations between vitamin D and skeletal myocyte size, and muscle regeneration. In vitro studies in skeletal muscle cells derived from mice and humans showed vitamin D played a role in regulating myoblast growth, size, and gene expression. Animal studies, primarily in mice, demonstrate vitamin D's positive effects on skeletal muscle function, such as improved grip strength and endurance. These studies encompass vitamin D diet research, genetically modified models, and disease-related mouse models. Relatively few studies looked at muscle function after injury, but these also support a role for vitamin D in muscle recovery. The human studies have also reported that vitamin D deficiency decreases muscle grip strength and gait speed, especially in the elderly population. Finally, human studies reported the benefits of vitamin D supplementation and achieving optimal serum vitamin D levels in muscle recovery after eccentric exercise and surgery. However, there were no benefits in rotator cuff injury studies, suggesting that repair mechanisms for muscle/ligament tears may be less reliant on vitamin D. In summary, vitamin D plays a crucial role in skeletal muscle function, structural integrity, and regeneration, potentially offering therapeutic benefits to patients with musculoskeletal diseases and in post-operative recovery.

Chicken plastination: its role in teaching avian anatomy

This paper describes the preparation of six plastinated chicken dissections for Veterinary Anatomy teaching at the University of Pretoria, South Africa. Specimens were fixed in 10% formalin for seven to ten days, depending on the size of the specimen. Room temperature acetone baths were used for dehydration over a period of six weeks. Impregnation in S10 took place over a period of three weeks at -16 °C. The specimens were cured with S6. A peristaltic pump was used during preparation to ensure the intestines were rinsed properly, and the chemicals penetrated the whole specimen. In the curing phase, a compressor was used to inflate the duodenum and small intestines to show the digestive and reproductive tracts. The plastinated specimens were then labelled. Three chicken hearts in different stages of dissection (one intact, one from the ventrum/cranial, one from the dorsum/caudal aspect) were prepared. A muscle dissection was carried out on a whole chicken with its intestines intact. It was found to be preferable to carry out the dissection while the specimen was stored in the acetone bath. When the dissection was complete, the body wall of the chicken was cut through with an oscillating saw before impregnation in S10. Another adult chicken was used for the skeleton. All the muscle was removed, and the skeleton placed in formalin for fixation. After a week, the skeleton was placed in acetone for dehydration. The aim with this skeleton was to show how the ligaments maintain skeletal integrity. The ovary and reproductive tract were also dissected. The plastinated specimens are now available to the students in the anatomical museum. Now students, at their own pace, may study and learn the anatomy of the chicken more intensely.

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis.

Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.

The Influences of Cryopreservation Methods on RNA, Protein, Microstructure and Cell Viability of Skeletal Muscle Tissue.

Background: Different experiments require different sample storage methods. The commonly used preservation methods in biobank practice cannot fully meet the multifarious requirements of experimental techniques. Programmable controlled slow freezing (PCSF) can maintain the viability of tissue. In this study, we hypothesized that PCSF-preserved samples have potential advantages in matching subsequent experiments compared with existing methods. Methods: We compared the differences on skeletal muscle tissue RNA integrity, protein integrity, microstructure integrity, and cell viability between four existing cryopreservation methods: liquid nitrogen (LN2) snap-freezing, LN2-cooled isopentane snap-freezing, RNAlater®-based freezing, and PCSF. RNA integrity was evaluated using agarose gel electrophoresis and RNA integrity number. Freezing-related microstructural damage in the muscle tissue was evaluated using ice crystal diameter and muscle fiber cross-sectional area. Protein integrity was evaluated using immunofluorescence staining. Cell viability was evaluated using trypan blue staining after primary muscle cell isolation. Results: PCSF preserved RNA integrity better than LN2 and isopentane, with a statistically significant difference. RNAlater preserved RNA integrity best. PCSF best controlled ice crystal size in myofibers, with a significant difference compared with LN2. The PCSF method best preserved the integrity of protein epitopes according to the mean fluorescence intensity results, with a significant difference. Cell viability was best preserved in the PCSF method compared with the other three methods, with a significant difference. Conclusion: PCSF protected the RNA integrity, microstructural integrity, protein integrity, and cell viability of skeletal muscle tissue. The application of PCSF in biobank practice is recommended as a multi-experiment-compatible cryopreservation method.

Skeletal effects following developmental flame-retardant exposure are specific to sex and chemical class in the adult Wistar rat.

Introduction: Accumulating evidence reveals that endocrine disrupting chemicals (EDCs) can disrupt aspects of metabolic programming, suggesting that skeletal development may be at risk, a possibility that is rarely examined. The commercial flame retardant (FR) mixture, Firemaster 550 (FM 550), has repeatedly been shown to negatively influence metabolic programming, raising concerns that skeletal integrity may consequently be impaired. We have previously shown that gestational and lactational exposure to 1,000µg FM 550 negatively affected sex-specific skeletal traits in male, but not female, rats assessed at 6months of age. Whether this outcome is primarily driven by the brominated (BFR) or organophosphate ester (OPFR) portions of the mixture or the effects persist to older ages is unknown. Materials and methods: To address this, in the present study, dams were orally exposed throughout gestation and lactation to either 1,000μg BFR, 1,000µg OPFR, or 2,000µg FM 550. Offspring (n = 8/sex/exposure) were weaned at PND 21 and assessed for femoral cortical and trabecular bone parameters at 8months of age by high-resolution X-ray micro-computed tomography (micro-CT). Serum levels of serotonin, osteocalcin, alkaline phosphatase, and calcium were quantified. Results: FM 550 affected both sexes, but the females were more appreciably impacted by the OPFRs, while the males were more vulnerable to the BFRs. Conclusion: Although sex specificity was expected due to the sexual dimorphic nature of skeletal physiology, the mechanisms accounting for the male- and female-specific phenotypes remain to be determined. Future work aims to clarify these unresolved issues.

Functional Reconstruction of Arches of the Foot With Vascularized Fibula Flap.

The skeletal integrity of the foot is as important as the soft tissue coverage of the foot. In this article, we present reconstruction of arches of foot with free fibula flap. Three patients with composite foot defects underwent reconstruction a with vascularized fibula flap. Free fibula flap was used to reconstruct the transverse arch in 2 cases and longitudinal arch in 1 case. The mean follow-up period was 3.2 years. Functional outcome was evaluated with 3-dimensional motion analyses at 12 months postoperatively. No early or late complications were encountered, and all patients were satisfied with both cosmetic appearance and functional aspects of their foot. Fibular bone showed a very healthy course without any fracture, resorption, extrusion, or migration. Three-dimensional motion analyses revealed acceptable gait capability in all cases showing successful restoration of the foot arches. As a conclusion, osteocutaneous free fibula flap can provide functional and durable reconstruction of longitudinal and transverse arches of the foot, especially if preservation of the length or the width of the foot is desired.

Resistance exercise: a mighty tool that adapts, destroys, rebuilds and modulates the molecular and structural environment of skeletal muscle.

Skeletal muscle regulates health and performance by maintaining or increasing strength and muscle mass. Although the molecular mechanisms in response to resistance exercise (RE) significantly target the activation of protein synthesis, a plethora of other mechanisms and structures must be involved in orchestrating the communication, repair, and restoration of homeostasis after RE stimulation. In practice, RE can be modulated by variations in intensity, continuity and volume, which affect molecular responses and skeletal muscle adaptation. Knowledge of these aspects is important with respect to planning of training programs and assessing the impact of RE training on skeletal muscle. In this narrative review, we introduce general aspects of skeletal muscle substructures that adapt in response to RE. We further highlighted the molecular mechanisms that control human skeletal muscle anabolism, degradation, repair and memory in response to acute and repeated RE and linked these aspects to major training variables. Although RE is a key stimulus for the activation of skeletal muscle anabolism, it also induces myofibrillar damage. Nevertheless, to increase muscle mass accompanied by a corresponding adaptation of the essential substructures of the sarcomeric environment, RE must be continuously repeated. This requires the permanent engagement of molecular mechanisms that re-establish skeletal muscle integrity after each RE-induced muscle damage. Various molecular regulators coordinately control the adaptation of skeletal muscle after acute and repeated RE and expand their actions far beyond muscle growth. Variations of key resistance training variables likely affect these mechanisms without affecting muscle growth.

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

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 (180ppm, 156 mice) from 7 to 22months 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.

Male Runners With Lower Energy Availability Have Impaired Skeletal Integrity Compared to Nonathletes.

Female athletes, particularly runners, with insufficient caloric intake for their energy expenditure [low energy availability (EA) or relative energy deficiency] are at risk for impaired skeletal integrity. Data are lacking in male runners. To determine whether male runners at risk for energy deficit have impaired bone mineral density (BMD), microarchitecture, and estimated strength. Cross-sectional. Clinical research center. 39 men (20 runners, 19 controls), ages 16-30 years. Areal BMD (dual-energy x-ray absorptiometry); tibia and radius volumetric BMD and microarchitecture (high-resolution peripheral quantitative computed tomography); failure load (microfinite element analysis); serum testosterone, estradiol, leptin; energy availability. Mean age (24.5 ± 3.8 y), lean mass, testosterone, and estradiol levels were similar; body mass index, percent fat mass, leptin, and lumbar spine BMD Z-score (-1.4 ± 0.8 vs -0.8 ± 0.8) lower (P < .05); and calcium intake and running mileage higher (P ≤ .01) in runners vs controls. Runners with EA <median had lower lumbar spine (-1.5 ± 0.7, P = .028), while runners with EA ≥median had higher hip (0.3 ± 0.7 vs -0.4 ± 0.5, P = .002), BMD Z-scores vs controls. After adjusting for calcium intake and running mileage, runners with EA <median had lower mean tibial total and trabecular volumetric BMD, trabecular bone volume fraction, cortical porosity, and apparent modulus vs controls (P < .05). Appendicular lean mass and serum estradiol (R ≥ 0.45, P ≤ .046), but not testosterone, were positively associated with tibial failure load among runners. Despite weight-bearing activity, skeletal integrity is impaired in male runners with lower caloric intake relative to exercise energy expenditure, which may increase bone stress injury risk. Lower estradiol and lean mass are associated with lower tibial strength in runners.