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Objective. Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) lead to inflammation in tendons and peritendinous tissues, but effects on biomechanical tendon function are unknown. This study investigated patellar tendon (PT) properties in stable, established RA and AS patients. Methods. We compared 18 RA patients (13 women, 59.0 ± 2.8 years, mean ± SEM) with 18 age- and sex-matched healthy controls (58.2 ± 3.2 years), and 12 AS patients (4 women, 52.9 ± 3.4 years) with 12 matched controls (54.5 ± 4.7 years). Assessments with electromyography, isokinetic dynamometry, and ultrasound included quadriceps muscle force and cross-sectional area (CSA), PT stiffness, and PT CSA. Additionally, measures of physical function and disease activity were performed. Results. PT stiffness and physical function were lower in RA and AS patients compared to healthy controls, without a significant difference in force production. PT CSA was significantly larger leading to reduction in Young’s modulus (YM) in AS, but not in RA. Conclusion. The adverse changes in PT properties in RA and AS may contribute to their impaired physical function. AS, but not RA, leads to PT thickening without increasing PT stiffness, suggesting that PT thickening in AS is a disorganised repair process. Longitudinal studies need to investigate the time course of these changes and their response to exercise training.

Continuous high glycemic load and inactivity challenge glucose homeostasis and fat oxidation. Hyperglycemia and high intramuscular glucose levels mediate insulin resistance, a precursor state of type 2 diabetes. The aim was to investigate whether a carbohydrate (CHO)-reduced diet combined with high-intensity interval training (HIIT) enhances the beneficial effects of the diet alone on insulin sensitivity and fat oxidation in obese individuals. Nineteen obese subjects underwent 14 days of CHO-reduced and energy-restricted diet. Ten of them combined the diet with HIIT (4 min bouts at 90% VO 2peak up to 10 times, 3 times a week). Oral glucose insulin sensitivity (OGIS) increased significantly in both groups; [diet–exercise (DE) group: pre 377 ± 70, post 396 ± 68 mL min −1  m −2 ; diet (D) group: pre 365 ± 91, post 404 ± 87 mL min −1  m −2 ; P  < 0.001]. Fasting respiratory exchange ratio (RER) decreased significantly in both groups (DE group: pre 0.91 ± 0.06, post 0.88 ± 0.06; D group: pre 0.92 ± 0.07, post 0.86 ± 0.07; P  = 0.002). VO 2peak increased significantly in the DE group (pre 27 ± 5, post 32 ± 6 mL kg −1  min −1 ; P  < 0.001), but not in the D group (pre 26 ± 9, post 26 ± 8 mL kg −1  min −1 ). Lean mass and resistin were preserved only in the DE group ( P  < 0.05). Fourteen days of CHO-reduced diet improved OGIS and fat oxidation (RER) in obese subjects. The energy-balanced HIIT did not further enhance these parameters, but increased aerobic capacity (VO 2peak ) and preserved lean mass and resistin.

Rheumatologic conditions featuring systemic inflammation are characterised by profound loss of physical function, which is in part caused by skeletal muscle wasting. This thesis aims to add to the current knowledge on disability in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) by determining the physiological properties of the tendon-muscle complex in these conditions, and by investigating causes of muscle loss in RA at the cellular level.The results section is divided into five main research chapters (chapters 3 to 7).Chapter 3 reports that physiological properties of muscle that determine specific force are preserved in a community-based population with stable RA compared to a healthy age- and sex-matched control group. Despite having deficits in physical function, no differences in vastus lateralis (VL) specific force, contractile properties, voluntary activation capacity and contraction velocity were observed in the RA patients. Body composition using DXA shows a trend towards lower appendicular lean mass and increased total body fat in patients relative to controls, and consistent with this, VL physiological cross-sectional area (PCSA) is reduced with RA (results published in Medicine and Science in Sports and Exercise 2010;42:2149-55).A considerable proportion of patients with RA are cachectic which indicates that processes have taken place which alter their muscle. Therefore, in Chapter 4 a group of cachectic RA patients was chosen to assess whether parameters of muscle quality are changed in these patients. However, the results show that even in cachectic RA patients, 3 muscle specific force and activation are not compromised compared with healthy age and sex-matched controls and thus are unlikely to contribute to the observed reduced function. As expected, VL PCSA and force were reduced (albeit non-significantly), and pennation angle also tended to be lower in RA. No differences were observed for muscle fibre fascicle length (results published in The Journal of Rheumatology 2010;37(2):282-84).Chapter 5. To investigate intracellular processes in the muscle of RA patients, biopsies were taken from the VL of patients with stable RA, healthy controls, and patients with active RA before and 3 months after achieving disease control. No differences were found in the distribution of myosin heavy chains (MHC) and in caspase-3, a marker of muscle apoptosis and atrophy, between stable RA patients and healthy controls. Thus, in concurrence with chapter 3 and 4, intracellular muscle quality was preserved in stable RA.In patients with active RA before and after disease control with the first-line diseasemodifying antirheumatic drug methotrexate or with anti-TNF agents ( etanercept or adalimumab), there was also no significant difference in caspase-3. However, pAkt, a key factor promoting muscle hypertrophy, was suppressed in patients with active RA compared to controlled disease in the same patients 3 months later, and could therefore be one of the principal reasons for muscle loss during the active phase of RA. In contrast to this, atrogin-1, a marker of muscle atrophy, was low in active disease as well, and IKBa, a downstream transcription factor ofTNF-a, did not change in patients with active disease before and after disease control. Thus, the complex mechanism leading to muscle atrophy in RA warrants further investigation.

Radiotherapy (RT) is applied in 45–60% of all cancer patients either alone or in multimodal therapy concepts comprising surgery, RT and chemotherapy. However, despite technical innovations approximately only 50% are cured, highlight a high medical need for innovation in RT practice. RT is a multidisciplinary treatment involving medicine and physics, but has always been successful in integrating emerging novel concepts from cancer and radiation biology for improving therapy outcome. Currently, substantial improvements are expected from integration of precision medicine approaches into RT concepts. Altered metabolism is an important feature of cancer cells and a driving force for malignant progression. Proper metabolic processes are essential to maintain and drive all energy-demanding cellular processes, e.g. repair of DNA double-strand breaks (DSBs). Consequently, metabolic bottlenecks might allow therapeutic intervention in cancer patients. Increasing evidence now indicates that oncogenic activation of metabolic enzymes, oncogenic activities of mutated metabolic enzymes, or adverse conditions in the tumor microenvironment can result in abnormal production of metabolites promoting cancer progression, e.g. 2-hyroxyglutarate (2-HG), succinate and fumarate, respectively. Interestingly, these so-called “oncometabolites” not only modulate cell signaling but also impact the response of cancer cells to chemotherapy and RT, presumably by epigenetic modulation of DNA repair. Here we aimed to introduce the biological basis of oncometabolite production and of their actions on epigenetic regulation of DNA repair. Furthermore, the review will highlight innovative therapeutic opportunities arising from the interaction of oncometabolites with DNA repair regulation for specifically enhancing the therapeutic effects of genotoxic treatments including RT in cancer patients.

Cancer resistance to chemotherapy, radiotherapy and molecular-targeted agents is a major obstacle to successful cancer therapy. Herein, aberrant activation of the phosphatidyl-inositol-3-kinase (PI3K)/protein kinase B (Akt) pathway is one of the most frequently deregulated pathways in cancer cells and has been associated with multiple aspects of therapy resistance. These include, for example, survival under stress conditions, apoptosis resistance, activation of the cellular response to DNA damage and repair of radiation-induced or chemotherapy-induced DNA damage, particularly DNA double strand breaks (DSB). One further important, yet not much investigated aspect of Akt-dependent signaling is the regulation of cell metabolism. In fact, many Akt target proteins are part of or involved in the regulation of metabolic pathways. Furthermore, recent studies revealed the importance of certain metabolites for protection against therapy-induced cell stress and the repair of therapy-induced DNA damage. Thus far, the likely interaction between deregulated activation of Akt, altered cancer metabolism and therapy resistance is not yet well understood. The present review describes the documented interactions between Akt, its target proteins and cancer cell metabolism, focusing on antioxidant defense and DSB repair. Furthermore, the review highlights potential connections between deregulated Akt, cancer cell metabolism and therapy resistance of cancer cells through altered DSB repair and discusses potential resulting therapeutic implications.

Oncogenic mutations in metabolic genes and associated oncometabolite accumulation support cancer progression but can also restrict cellular functions needed to cope with DNA damage. For example, gain-of-function mutations in isocitrate dehydrogenase (IDH) and the resulting accumulation of the oncometabolite D-2-hydroxyglutarate (D-2-HG) enhanced the sensitivity of cancer cells to inhibition of poly(ADP-ribose)-polymerase (PARP)1 and radiotherapy (RT). In our hand, inhibition of the mitochondrial citrate transport protein (SLC25A1) enhanced radiosensitivity of cancer cells and this was associated with increased levels of D-2-HG and a delayed repair of radiation-induced DNA damage. Here we aimed to explore the suggested contribution of D-2-HG-accumulation to disturbance of DNA repair, presumably homologous recombination (HR) repair, and enhanced radiosensitivity of cancer cells with impaired SLC25A1 function. Genetic and pharmacologic inhibition of SLC25A1 (SLC25A1i) increased D-2-HG-levels and sensitized lung cancer and glioblastoma cells to the cytotoxic action of ionizing radiation (IR). SLC25A1i-mediated radiosensitization was abrogated in MEFs with a HR-defect. D-2-HG-accumulation was associated with increased DNA damage and delayed resolution of IR-induced γH2AX and Rad51 foci. Combining SLC25A1i with PARP- or the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs)-inhibitors further potentiated IR-induced DNA damage, delayed DNA repair kinetics resulting in radiosensitization of cancer cells. Importantly, proof of concept experiments revealed that combining SLC25A1i with IR without and with PARPi also reduced tumor growth in the chorioallantoic membrane (CAM) model in vivo. Thereby SLC25A1i offers an innovative strategy for metabolic induction of context-dependent lethality approaches in combination with RT and clinically relevant inhibitors of complementary DNA repair pathways.

Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disease in humans. However, the pathogenesis of ALS is not yet understood. The wobbler mouse is considered as an animal model for the sporadic form of ALS due to its spontaneous mutation in the Vps54 gene. Due to transactivation of NDRG2 by p53, this tumor suppressor might play a functional role in stress induced cell death in wobbler mice as well as ALS patients. Furthermore, deregulated microRNAs are often related to neurodegenerative diseases. Thus, the NDRG2 linked miR-375-3p was of interest for this study. Here, we investigated the relevance of NDRG2 and miR-375-3p for the pathomechanism of the motor neuronal degeneration in wobbler mice by investigating expression level via qPCR and Western Blot as well as localization of these molecules in the cervical spinal cord by in situ hybridization, immunostaining and mass spectrometric analysis. We were able to show a differential regulation of the expression of NDRG2 as well as miR-375-3p in the cervical part of the spinal cord of wobbler mice. In addition, for the first time we were able to demonstrate an expression of NDRG2 in motor neurons using different techniques. The present study has shown NDRG2 and miR-375-3p to be promising targets for further research of the pathogenesis of sporadic ALS in the wobbler mouse model. Based on these results and in combination with previous published data we could develop a putative pro-apoptotic mechanism in the spinal cord of the wobbler mouse.

Although the enteric nervous system (ENS) functions largely autonomously as part of the peripheral nervous system (PNS), it is connected to the central nervous system (CNS) via the gut–brain axis. In many neurodegenerative diseases, pathological changes occur in addition to gastrointestinal symptoms, such as alpha-synuclein aggregates in Parkinson’s disease, which are found early in the ENS. In both the CNS and PNS, vascular endothelial growth factor (VEGF) mediates neuroprotective and neuroregenerative effects. Since the ENS with its close connection to the microbiome and the immune system is discussed as the origin of neurodegenerative diseases, it is necessary to investigate the possibly positive effects of VEGF on enteric neurons. Using laser microdissection and subsequent quantitative RT-PCR as well as immunohistochemistry, for the first time we were able to detect and localize VEGF receptor expression in rat myenteric neurons of different ages. Furthermore, we demonstrate direct neuroprotective effects of VEGF in the ENS in cell cultures. Thus, our results suggest a promising approach regarding neuroprotection, as the use of VEGF (may) prevent neuronal damage in the ENS.

Metabolic rewiring is the result of the increasing demands and proliferation of cancer cells, leading to changes in the biological activities and responses to treatment of cancer cells. The mitochondrial citrate transport protein SLC25A1 is involved in metabolic reprogramming offering a strategy to induce metabolic bottlenecks relevant to radiosensitization through the accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) upon SLC25A1 inhibition (SLC25A1i). Previous studies have revealed the comparative effects of SLC25A1i or cell-permeable D-2HG (octyl-D-2HG) treatments on DNA damage induction and repair, as well as on energy metabolism and cellular function, which are crucial for the long-term survival of irradiated cells. Here, α-ketoglutarate (αKG), the precursor of D-2HG, potentiated the effects observed upon SLC25A1i on DNA damage repair, cell function and long-term survival in vitro and in vivo, rendering NCI-H460 cancer cells more vulnerable to ionizing radiation. However, αKG treatment alone had little effect on these phenotypes. In addition, supplementation with nicotinamide (NAM), a precursor of NAD (including NAD + and NADH), counteracted the effects of SLC25A1i or the combination of SLC25A1i with αKG, highlighting a potential importance of the NAD + /NADH balance on cellular activities relevant to the survival of irradiated cancer cells upon SLC25A1i. Furthermore, inhibition of histone lysine demethylases (KDMs), as a major factor affected upon SLC25A1i, by JIB04 treatment alone or in combination with αKG supplementation phenocopied the broad effects on mitochondrial and cellular function induced by SLC25A1i. Taken together, αKG supplementation potentiated the effects on cellular processes observed upon SLC25A1i and increased the cellular demand for NAD to rebalance the cellular state and ensure survival after irradiation. Future studies will elucidate the underlying metabolic reprogramming induced by SLC25A1i and provide novel therapeutic strategies for cancer treatment.

Background Cutaneous melanoma is the most aggressive type of skin cancer, with survival rates declining due to tumor heterogeneity and therapy resistance. Distinct subpopulations, including slow-cycling, therapy-resistant cells with high expression of the histone demethylase KDM5B, contribute to tumor progression and poor outcomes. Intermittent cycling hypoxia, defined by repeated hypoxia followed by reoxygenation, promotes tumor plasticity and aggressiveness, yet its role in melanoma heterogeneity and resistance remains poorly understood. Methods We established hypoxia/reoxygenation-tolerant (HRT) melanoma cell lines (Hx10) through 10 cycles of intermittent cycling hypoxia (48 h at 0.2% O₂ followed by 120 h at 20.9% O₂) under conditions of KDM5B overexpression. Radiation response was evaluated in Hx10 and nonselected control cells. To investigate adaptive mechanisms, we performed reversed-phase protein array (RPPA) screening and applied an information-theoretic approach to compute protein-specific altered signaling signatures. Pathway enrichment analyses were used to identify dysregulated subnetworks. Results Hx10 melanoma cells displayed increased resistance to radiation compared with nonselected control cells. Proteomic profiling identified distinct signaling signatures associated with KDM5B overexpression and adaptation to cycling hypoxia. These signatures revealed coexpressed subnetworks involving DNA repair, PI3K/AKT/mTOR, AMPK, and autophagy pathways, several of which are implicated in therapy resistance. Functional assays demonstrated that targeting either KDM5B or PI3K reduced the radioresistance of Hx10 melanoma cells. Sequential combination treatments impaired repopulation ability, particularly when KDM5B overexpression was withdrawn, indicating dependence on KDM5B for survival. Conclusions Our findings provide proof-of-concept that altered signaling signatures can be used to define novel vulnerabilities in melanoma. KDM5B overexpression promotes adaptation to intermittent cycling hypoxia and confers resistance to radiation through activation of DNA repair and survival pathways. Targeting KDM5B or PI3K in combination with radiotherapy may represent a promising strategy to overcome resistance and improve treatment outcomes in melanoma.