IU Indianapolis ScholarWorks :: Browsing by Subject "Muscle"

Browsing by Subject "Muscle"

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Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice
(Frontiers Media, 2019-11-19) Essex, Alyson L.; Pin, Fabrizio; Huot, Joshua R.; Bonewald, Lynda F.; Plotkin, Lilian I.; Bonetto, Andrea; Anatomy and Cell Biology, School of Medicine
Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mechanisms also take place following treatments with anticancer drugs. In this study, we found that young male CD2F1 mice (8-week old) treated with the chemotherapeutic agent cisplatin (2.5 mg/kg) presented marked loss of muscle and bone mass. Myotubes exposed to bone conditioned medium from cisplatin-treated mice showed severe atrophy (−33%) suggesting a bone to muscle crosstalk. To test this hypothesis, mice were administered cisplatin in combination with an antiresorptive drug to determine if preservation of bone mass has an effect on muscle mass and strength following chemotherapy treatment. Mice received cisplatin alone or combined with zoledronic acid (ZA; 5 μg/kg), a bisphosphonate routinely used for the treatment of osteoporosis. We found that cisplatin resulted in progressive loss of body weight (−25%), in line with reduced fat (−58%) and lean (−17%) mass. As expected, microCT bone histomorphometry analysis revealed significant reduction in bone mass following administration of chemotherapy, in line with reduced trabecular bone volume (BV/TV) and number (Tb.N), as well as increased trabecular separation (Tb.Sp) in the distal femur. Conversely, trabecular bone was protected when cisplatin was administered in combination with ZA. Interestingly, while the animals exposed to chemotherapy presented significant muscle wasting (~-20% vs. vehicle-treated mice), the administration of ZA in combination with cisplatin resulted in preservation of muscle mass (+12%) and strength (+42%). Altogether, these observations support our hypothesis of bone factors targeting muscle and suggest that pharmacological preservation of bone mass can benefit muscle mass and function following chemotherapy.
COVID-19 and Bone Loss: A Review of Risk Factors, Mechanisms, and Future Directions
(Springer, 2024) Creecy, Amy; Awosanya, Olatundun D.; Harris, Alexander; Qiao, Xian; Ozanne, Marie; Toepp, Angela J.; Kacena, Melissa A.; McCune, Thomas; Orthopaedic Surgery, School of Medicine
Purpose of review: SARS-CoV-2 drove the catastrophic global phenomenon of the COVID-19 pandemic resulting in a multitude of systemic health issues, including bone loss. The purpose of this review is to summarize recent findings related to bone loss and potential mechanisms. Recent findings: The early clinical evidence indicates an increase in vertebral fractures, hypocalcemia, vitamin D deficiencies, and a loss in BMD among COVID-19 patients. Additionally, lower BMD is associated with more severe SARS-CoV-2 infection. Preclinical models have shown bone loss and increased osteoclastogenesis. The bone loss associated with SARS-CoV-2 infection could be the result of many factors that directly affect the bone such as higher inflammation, activation of the NLRP3 inflammasome, recruitment of Th17 cells, the hypoxic environment, and changes in RANKL/OPG signaling. Additionally, SARS-CoV-2 infection can exert indirect effects on the skeleton, as mechanical unloading may occur with severe disease (e.g., bed rest) or with BMI loss and muscle wasting that has also been shown to occur with SARS-CoV-2 infection. Muscle wasting can also cause systemic issues that may influence the bone. Medications used to treat SARS-CoV-2 infection also have a negative effect on the bone. Lastly, SARS-CoV-2 infection may also worsen conditions such as diabetes and negatively affect kidney function, all of which could contribute to bone loss and increased fracture risk. SARS-CoV-2 can negatively affect the bone through multiple direct and indirect mechanisms. Future work will be needed to determine what patient populations are at risk of COVID-19-related increases in fracture risk, the mechanisms behind bone loss, and therapeutic options. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
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 Sciences
Purpose 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.
Electrical stimulation of hindlimb skeletal muscle has beneficial effects on sublesional bone in a rat model of spinal cord injury
(Elsevier, 2021) Zhao, Wei; Peng, Yuanzhen; Hu, Yizhong; Guo, X. Edward; Li, Jiliang; Cao, Jay; Pan, Jiangping; Feng, Jian Q.; Cardozo, Christopher; Jarvis, Jonathan; Bauman, William A.; Qin, Weiping; Anatomy, Cell Biology and Physiology, School of Medicine
Spinal cord injury (SCI) results in marked atrophy of sublesional skeletal muscle and substantial loss of bone. In this study, the effects of prolonged electrical stimulation (ES) and/or testosterone enanthate (TE) on muscle mass and bone formation in a rat model of SCI were tested. Compared to sham-transected animals, a significant reduction of the mass of soleus, plantaris and extensor digitorum longus (EDL) muscles was observed in animals 6 weeks post-SCI. Notably, ES or ES + TE resulted in the increased mass of the EDL muscles. ES or ES + TE significantly decreased mRNA levels of muscle atrophy markers (e.g., MAFbx and MurF1) in the EDL. Significant decreases in bone mineral density (BMD) (-27%) and trabecular bone volume (-49.3%) at the distal femur were observed in animals 6 weeks post injury. TE, ES and ES + TE treatment significantly increased BMD by +6.4%, +5.4%, +8.5% and bone volume by +22.2%, and +56.2% and+ 60.2%, respectively. Notably, ES alone or ES + TE resulted in almost complete restoration of cortical stiffness estimated by finite element analysis in SCI animals. Osteoblastogenesis was evaluated by colony-forming unit-fibroblastic (CFU-F) staining using bone marrow mesenchymal stem cells obtained from the femur. SCI decreased the CFU-F+ cells by -56.8% compared to sham animals. TE or ES + TE treatment after SCI increased osteoblastogenesis by +74.6% and +67.2%, respectively. An osteoclastogenesis assay revealed significantly increased TRAP+ multinucleated cells (+34.8%) in SCI animals compared to sham animals. TE, ES and TE + ES treatment following SCI markedly decreased TRAP+ cells by -51.3%, -40.3% and -46.9%, respectively. Each intervention greatly reduced the ratio of RANKL to OPG mRNA of sublesional long bone. Collectively, our findings demonstrate that after neurologically complete paralysis, dynamic muscle resistance exercise by ES reduced muscle atrophy, downregulated genes involved in muscle wasting, and restored mechanical loading to sublesional bone to a degree that allowed for the preservation of bone by inhibition of bone resorption and/or by facilitating bone formation.
Ex Vivo Organ Cultures as Models to Study Bone Biology
(Wiley, 2020-02-14) Bellido, Teresita; Delgado-Calle, Jesus; Anatomy and Cell Biology, School of Medicine
The integrity of the skeleton is maintained by the coordinated and balanced activities of the bone cells. Osteoclasts resorb bone, osteoblasts form bone, and osteocytes orchestrate the activities of osteoclasts and osteoblasts. A variety of in vitro approaches has been used in an attempt to reproduce the complex in vivo interactions among bone cells under physiological as well as pathological conditions and to test new therapies. Most cell culture systems lack the proper extracellular matrix, cellular diversity, and native spatial distribution of the components of the bone microenvironment. In contrast, ex vivo cultures of fragments of intact bone preserve key cell–cell and cell–matrix interactions and allow the study of bone cells in their natural 3D environment. Further, bone organ cultures predict the in vivo responses to genetic and pharmacologic interventions saving precious time and resources. Moreover, organ cultures using human bone reproduce human conditions and are a useful tool to test patient responses to therapeutic agents. Thus, these ex vivo approaches provide a platform to perform research in bone physiology and pathophysiology. In this review, we describe protocols optimized in our laboratories to establish ex vivo bone organ cultures and provide technical hints and suggestions. In addition, we present examples on how this technical approach can be employed to study osteocyte biology, drug responses in bone, cancer‐induced bone disease, and cross‐talk between bone and other organs.
Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia
(American Society for Clinical Investigation, 2020-04-16) Huot, Joshua R.; Novinger, Leah J.; Pin, Fabrizio; Narasimhan, Ashok; Zimmers, Teresa A.; O’Connell, Thomas M.; Bonetto, Andrea; Surgery, School of Medicine
Advanced colorectal cancer (CRC) is often accompanied by development of liver metastases (LMs) and skeletal muscle wasting (i.e., cachexia). Despite plaguing the majority of CRC patients, cachexia remains unresolved. By using mice injected with Colon-26 mouse tumors, either subcutaneously (s.c.; C26) or intrasplenically to mimic hepatic dissemination of cancer cells (mC26), here we aimed to further characterize functional, molecular, and metabolic effects on skeletal muscle and examine whether LMs exacerbate CRC-induced cachexia. C26-derived LMs were associated with progressive loss of body weight, as well as with significant reductions in skeletal muscle size and strength, in line with reduced phosphorylation of markers of protein anabolism and enhanced protein catabolism. mC26 hosts showed prevalence of fibers with glycolytic metabolism and enhanced lipid accumulation, consistent with abnormalities of mitochondrial homeostasis and energy metabolism. In a comparison with mice bearing s.c. C26, cachexia appeared exacerbated in the mC26 hosts, as also supported by differentially expressed pathways within skeletal muscle. Overall, our model recapitulates the cachectic phenotype of metastatic CRC and reveals that formation of LMs resulting from CRC exacerbate cancer-induced skeletal muscle wasting by promoting differential gene expression signatures.
Glucocorticoid induced osteoporosis and mechanisms of intervention
(2017-03) Sato, Amy Yoshiko; Bellido, Teresita; Plotkin, Lilian I.; Pavalko, Fredrick M.; Robling, Alexander G.
Glucocorticoid excess is a leading cause of osteoporosis. The loss of bone mass and strength corresponds to the increase in fractures exhibited after three months of glucocorticoid therapy. Glucocorticoids induce the bone cellular responses of deceased bone formation, increased osteoblast/osteocyte apoptosis, and transient increased bone resorption, which result in rapid bone loss and degradation of bone microarchitecture. The current standard of care for osteoporosis is bisphosphonate treatment; however, these agents further suppress bone formation and increase osteonecrosis and low energy atypical fracture risks. Thus, there is an unmet need for interventions that protect from glucocorticoid therapy. The purpose of these studies was to investigate novel mechanisms that potentially interfere with glucocorticoid-induced bone loss. We chose to explore pathways that regulate endoplasmic reticulum stress, the canonical Wnt pathway, and Pyk2 activity. Pharmacologic reduction of endoplasmic reticulum stress through salubrinal administration protected against glucocorticoid-induced bone loss by preservation of bone formation and osteoblast/osteocyte viability. In contrast, inhibition of Wnt antagonist Sost/sclerostin and inhibition of Pyk2 signaling did not prevent glucocorticoid-induced reductions in bone formation; however, both Sost/sclerostin and Pyk2 deficiency protected against bone loss through inhibition of increases in resorption. Overall, these studies demonstrate the significant contributions of reductions in bone formation, increased osteoblast/osteocyte apoptosis, and elevations in resorption to the rapid 6-12% bone loss exhibited during the first year of glucocorticoid therapy. However, glucocorticoid excess also induces skeletal muscle weakness, which is not reversed by bisphosphonate treatment or the interventions reported here of salubrinal, Sost/sclerostin inhibition, or Pyk2 deficiency. Further, the novel finding of increased E3 ubiquitin ligase atrophy signaling induce by glucocorticoids in both bone and muscle, by tissue-specific upstream mechanisms, provides opportunities for therapeutic combination strategies. Thus, future studies are warranted to investigate the role of E3 ubiquitin ligase signaling in the deleterious glucocorticoid effects of bone and muscle.
A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase
(Elsevier, 2017-01) Maile, C.A.; Hingst, J. R.; Mahalingan, K. K.; O'Reilly, A. O.; Cleasby, M. E.; Mickelson, J. R.; McCue, M. E.; Anderson, S. M.; Hurley, T. D.; Wojtaszewski, J. F. P.; Piercy, R. J.; Biochemistry and Molecular Biology, School of Medicine
BACKGROUND: Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle. METHODS: Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change. RESULTS: PSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower Km for UDP-glucose, in the presence and absence of G6P, when compared to wild type GS, and despite its phosphorylation. CONCLUSIONS: Elevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state. GENERAL SIGNIFICANCE: This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy.
Increased Adenine Nucleotide Degradation in Skeletal Muscle Atrophy
(MDPI, 2019-12-21) Miller, Spencer G.; Hafen, Paul S.; Brault, Jeffrey J.; Anatomy and Cell Biology, School of Medicine
Adenine nucleotides (AdNs: ATP, ADP, AMP) are essential biological compounds that facilitate many necessary cellular processes by providing chemical energy, mediating intracellular signaling, and regulating protein metabolism and solubilization. A dramatic reduction in total AdNs is observed in atrophic skeletal muscle across numerous disease states and conditions, such as cancer, diabetes, chronic kidney disease, heart failure, COPD, sepsis, muscular dystrophy, denervation, disuse, and sarcopenia. The reduced AdNs in atrophic skeletal muscle are accompanied by increased expression/activities of AdN degrading enzymes and the accumulation of degradation products (IMP, hypoxanthine, xanthine, uric acid), suggesting that the lower AdN content is largely the result of increased nucleotide degradation. Furthermore, this characteristic decrease of AdNs suggests that increased nucleotide degradation contributes to the general pathophysiology of skeletal muscle atrophy. In view of the numerous energetic, and non-energetic, roles of AdNs in skeletal muscle, investigations into the physiological consequences of AdN degradation may provide valuable insight into the mechanisms of muscle atrophy.
Investigation into Tissue-Specific Mechanisms of Mitochondrial Dysfunction: Models of SUCLA2 Deficiency and a Screen for Potential Genetic Modifiers
(2023-11) Lancaster, Makayla S.; Graham, Brett H.; Kim, Jungsu; Hoffman-Longtin, Krista; White, Kenneth E.
With no currently effective treatments available, mitochondrial diseases are one of the most common forms of inherited multisystem disease. Primary disorders of the mitochondria affect an estimated 1 in 4,300 people with typical onset in early childhood. Mitochondrial disorders are classically defined by defects in the mitochondrial powerhouse, or respiratory chain (RC). Therefore, they are uniquely complex as the proteins within the RC are encoded by two separate genomes – nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). The mitochondrial genome encodes 13 protein genes within the RC, with the remaining mitochondrial proteome being nuclear encoded. Therefore, mitochondrial disorders result from pathogenic variants within either genome. While mitochondrial disorders can affect multiple tissue symptoms, organs with high energy demand, such as the brain and skeletal muscle, are most typically affected; thus, mitochondrial disease typically manifests as an encephalomyopathy. A wide range of symptoms, including developmental delay, seizures, strokes, and sensorineural hearing loss have been associated with mitochondrial dysfunction. In short, however, investigation into the pathogenic mechanisms of mitochondrial disorders has proven difficult due to the wide clinical and genetic heterogeneity associated with the disorders. Therefore, this project seeks to investigate pathways of mitochondrial dysfunction using two genetic approaches. First, reverse genetics tools are used to generate tissue-specific mouse models of succinyl-CoA synthetase deficiency, which is a known cause of mitochondrial disease in humans. In parallel, forward genetics is used to screen for variation in mitochondrial phenotypes in a genetically diverse population of mice to identify potential genetic modifiers of mitochondrial function and health. Using both forward and reverse genetics approaches, these studies will allow for the investigation into tissue-specific mitochondrial pathogenesis in novel mouse models, as well as broadly characterize tissue-specific mitochondrial function in vivo. Taken together, both genetic approaches are used to broaden understanding of tissue-specific mitochondrial function in health and disease.

Browsing by Subject "Muscle"

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