Time-dependent reduction in oxidative capacity among cultured myotubes from spinal cord injured individuals.

BACKGROUND: Skeletal muscle adapts in reaction to contractile activity to efficiently utilize energy substrates, primarily glucose and free fatty acids (FA). Inactivity leads to atrophy and a change in energy utilization in individuals with spinal cord injury (SCI). The present study aimed to characterize possible inactivity-related differences in the energy metabolism between skeletal muscle cells cultured from satellite cells isolated 1- and 12-months post-SCI. METHODS: To characterize inactivity-related disturbances in spinal cord injury, we studied skeletal muscle cells isolated from SCI subjects. Cell cultures were established from biopsy samples from musculus vastus lateralis from subjects with SCI 1 and 12 months after the injury. The myoblasts were proliferated and differentiated into myotubes before fatty acid and glucose metabolism were assessed and gene and protein expressions were measured. RESULTS: The results showed that glucose uptake was increased, while oleic acid oxidation was reduced at 12 months compared to 1 month. mRNA expressions of PPARGC1α, the master regulator of mitochondrial biogenesis, and MYH2, a determinant of muscle fiber type, were significantly reduced at 12 months. Proteomic analysis showed reduced expression of several mitochondrial proteins. CONCLUSION: In conclusion, skeletal muscle cells isolated from immobilized subjects 12 months compared to 1 month after SCI showed reduced fatty acid metabolism and reduced expression of mitochondrial proteins, indicating an increased loss of oxidative capacity with time after injury.

Increased cancer incidence and mortality among people with opioid use-related disorders: A nation-wide cohort study.

BACKGROUND AND AIMS: Studies on cancer incidence and mortality among people with opioid use-related disorders are lacking. We aimed to measure cancer-specific incidence, mortality and survival among people diagnosed with opioid use-related disorders in Norway during 2010-18. DESIGN AND SETTING: This was a cohort study conducted in Norway during 2010-18. PARTICIPANTS: Individuals (n = 20 710) diagnosed with opioid use-related disorders. MEASUREMENTS: We conducted a cohort study utilizing a data-linkage of national health and population registers. Information on opioid use-related disorders was extracted from specialized healthcare, malignancies from the Cancer Registry of Norway and deaths from Cause of Death Registry. Cancer incidence and mortality were compared with the general population by calculating sex-specific age-standardized incidence (SIR) and mortality (SMR) ratios. One-year survival rates were computed. FINDINGS: Compared with the general population, people with opioid use-related disorders were at an increased risk of developing cancer overall [SIR = 1.2, 95% confidence interval (CI) = 1.1-1.3] with a higher than twofold cancer mortality rate (SMR = 2.3, 95% CI = 2.0-2.7). Excess risk was observed for liver (12.6, 95% CI = 9.1-17.0), larynx (4.7, 95% CI = 1.7-10.2), lung (3.5, 95% CI = 2.8-4.3) and pancreas cancer (2.6, 95% CI = 1.6-4.0), whereas reduced risk was found for melanoma (0.5, 95% CI = 0.3-0.9), breast (0.6, 95% CI = 0.4-0.9) and prostate cancers (0.3, 95% CI = 0.1-0.4). Site-specific SMRs were significantly elevated for liver (12.3, 95% CI = 8.5-17.2), lung (3.9, 95% CI = 3.0-5.0), pancreas (3.0, 95% CI = 1.7-4.8) and colon cancers (1.9, 95% CI = 1.1-3.1). The average 1-year survival rate after a cancer diagnosis was low in liver, pancreas and colon cancer, ranging from 10 to 15% less than that of the general population. CONCLUSIONS: In Norway, cancer incidence and cancer-related mortality appear to be elevated among individuals with opioid use-related disorders.

Acute changes in antioxidants and oxidative stress to vigorous arm exercise: an intervention trial in persons with spinal cord injury and healthy controls.

STUDY DESIGN: Intervention trial. BACKGROUND: Literature remains unclear on possible health benefits and risks assosciated with high intensity exercise for persons with SCI. Elevated oxidative stress levels might influence their ability to exercise at high intensity. We investigated several biomarkers of oxidative stress and antioxidant defense at rest, during and after vigorous exercise among persons with chronic SCI. SETTING: Sunnaas Rehabilitation Hospital, Norway. METHODS: Six participants (five males) with chronic SCI (AIS A, injury level thoracic 2-8, >1 year postinjury) and six matched able-bodied controls performed two maximal arm-cranking tests, with one-three days in between. During the second exercise test, participants performed three bouts with four minutes arm cranking at high intensity (85-95% of peak heart rate (HRpeak)), before they reached maximal effort. Blood and urine biomarkers for oxidative stress and antioxidant levels were collected at six time points at the day of the second exercise test; baseline, at high intensity exercise, at maximal effort, at five, 30 and 60 min post-exercise, and 24 h post exercise. RESULTS: Participants with SCI had significant lower levels of creatinine (∆16 µmol/L, p = 0.03), α-carotene (∆0.14 nmol/L, p < 0.001) and ß-carotene (∆0.51 nmol/L, p = 0.001) at baseline compared to controls. Urine and blood biomarkers of oxidative stress and antioxidant levels showed similar response to vigorous exercise in the SCI and control group. CONCLUSIONS: SCI participants showed similar changes in redox status during high intensity exercise compared to matched able-bodied. SCI participants had lower levels of exogen antioxidants both before, during and after vigorous exercise.

Community dwelling life- and health issues among persons living with chronic spinal cord injury in North Macedonia.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: The purpose was to reveal late health consequences and life issues after a traumatic spinal cord injury (tSCI) in North Macedonia (NM). SETTING: Community dwelling adults with tSCI in NM. METHODS: Persons that sustained tSCI in 1999-2005 were selected, physical examined and a questionnaire was administered. Descriptive statistics were conducted. RESULTS: From 203 eligible persons, 40 agreed to participate. Mean (range) age at time of injury was 36 (27-75) years and time since injury ranged 9-20 years. Around seventy percent reported current health problems, of which pain and spasm (>60%) were most prevalent, followed by urinary tract infections and pressure injuries. About 30% had never been to a medical specialist and ≈70% had only once been to physiotherapy after discharge from the primary inpatient period. Only one participant had a fully adjusted home for a person with a disability. Those with most severe tSCI (American Spinal Injury Association Impairment Scale (AIS) A, B, and C) seldom left their homes. About 50% were retired and/or unemployed, 50% were working. CONCLUSION: This is the first study describing community-dwelling persons with a tSCI in NM. Our study revealed that persons with tSCI reported health issues mostly related to pain, spasms, urinary tract infections and pressure injuries. They lacked follow-ups, experienced physical barriers and poor inclusion in the society, and lacked financial support. Therefore, they were often socially isolated and fully dependent on their families. NM is in need of structured rehabilitation programs and better adaption for persons with reduced mobility.

Epidemiological characteristics and early complications after spinal cord injury in Former Yugoslav Republic of Macedonia.

STUDY DESIGN: Prospective cohort study OBJECTIVES: To describe epidemiological data and complications after acute traumatic spinal cord injury (tSCI) in Former Yugoslav Republic of Macedonia (FYROM). SETTING: University Clinic for Traumatology, Orthopedics, Anesthesia and Intensive Care Unit and Emergency Center (TOARILUC), Mother Teresa, Skopje, FYROM. METHOD: During the inclusion period March 2015 to September 2016, 38 tSCI patients were included. MRI, CT scan, and clinical examinations including International Standards for Neurological Classification of SCI were performed at admission. The information included: demographic data, transport type, date of admission and discharge, past illnesses, addiction habits, cause and type of injury, injury level, associated injuries, injury-related complications, and mortality. RESULTS: Mean age was 43 years (median 41, range 17-83). Seventeen patients had a complete and 15 an incomplete SCI, six were unknown. Most frequent causes for tSCI were traffic accidents (42%) and falls (40%), 24% of the accidents were contracted at work. Sixteen patients were ventilator dependent at some point during the acute period. Common complications were pressure ulcers, gastrointestinal-related, and infections. Hospital length of stay (LOS) ranged from 1 to 73 days. The in-hospital mortality rate was 32%. CONCLUSION: The annual incidence of tSCI in FYROM was in 2015-16 13 persons/million inhabitants per year. The epidemiological profile of tSCI in FYROM implies that preventive measures should be taken to reduce incidence of accidents in traffic and at work places. The high mortality rate and complications underline further actions to improve the acute care of tSCI in FYROM.

Cross-sectional and prospective data-collection in North Macedonia-methodological considerations.

Study design: Cross-sectional and prospective cohort-study. Objectives: To describe methodological issues, experienced challenges related to data collection in North Macedonia and to discuss possible improvements of epidemiological data collection in future studies. Setting: Clinic for Traumatology, Orthopedics, Anesthesia, Reanimation, Intensive Care Unit and Emergency Center, Mother Teresa Skopje University Hospital, Skopje and community settings, North Macedonia. Method: A description of methodological challenges experienced in collecting data from 78 persons with acute and chronic traumatic spinal cord injury (SCI) examined and interviewed in 2015-2017 using a semiquantitative questionnaire and standard assessments tools. Results: This study identified three major challenges with data collection in this setting: (1) research logistics and procedures, such as recruitment, infrastructure, and compensation, (2) ethical issues and the initial lack of mutual trust and understanding between researchers and participants, and (3) scientific quality and interpretation, including representativeness. Conclusions: Methodological issues influenced by settings, are important to consider when interpreting study results. Healthcare systems vary between (and sometimes in) countries, language and culture may introduce barriers to understanding, and epidemiological research also rely on infrastructure and surroundings. For this study, making time for and listening to the participants without being intruding was of special importance in building trust and a good relationship with the participants during recruiting participants and collecting data. We here provide suggestions regarding how to facilitate future epidemiological data collections in North Macedonia.

Altered oxidative stress and antioxidant defence in skeletal muscle during the first year following spinal cord injury.

Oxidative stress promotes protein degradation and apoptosis in skeletal muscle undergoing atrophy. We aimed to determine whether spinal cord injury leads to changes in oxidative stress, antioxidant capacity, and apoptotic signaling in human skeletal muscle during the first year after spinal cord injury. Vastus lateralis biopsies were obtained from seven individuals 1, 3, and 12 months after spinal cord injury and from seven able-bodied controls. Protein content of enzymes involved in reactive oxygen species production and detoxification, and apoptotic signaling were analyzed by western blot. Protein carbonylation and 4-hydroxynonenal protein adducts were measured as markers of oxidative damage. Glutathione content was determined fluorometrically. Protein content of NADPH oxidase 2, xanthine oxidase, and pro-caspase-3 was increased at 1 and 3 months after spinal cord injury compared to able-bodied controls. Furthermore, total and reduced glutathione content was increased at 1 and 3 months after spinal cord injury. Conversely, mitochondrial complexes and superoxide dismutase 2 protein content were decreased 12 months after spinal cord injury compared to able-bodied controls. In conclusion, we provide indirect evidence of increased reactive oxygen species production and increased apoptotic signaling at 1 and 3 months after spinal cord injury. Concomitant increases in glutathione antioxidant defences may reflect adaptations poised to maintain redox homeostasis in skeletal muscle following spinal cord injury.

Carboxy terminal collagen crosslinks as a prognostic risk factor for fall-related fractures in individuals with established spinal cord injury.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To study associations between specific bone turnover markers and fall-related fractures in individuals with spinal cord injury (SCI). SETTING: Rehabilitation Hospital. METHODS: Carboxy terminal collagen crosslinks (CTX), type-1 procollagen N-terminal (P1NP), albumin-corrected calcium (Ca2+), parathyroid hormone (PTH) and vitamin D were examined in a cohort of 106 participants with SCI at least 1 year post injury. The participants were followed for 1 year monitoring fall-related fractures. RESULTS: In total, 29 out of 106 reported having experienced a fall-related fracture post-injury at baseline, and 5 out of 100 had experienced a fall-related bone fracture during the 1 year follow-up. Our main findings were that high levels of serum CTX increased the odds of being in the fracture group, and that 25-hydroxy vitamin D (25 OHD) levels, Ca2+, PTH or P1NP were not associated with being in the fracture group. CONCLUSIONS: We here present an association between high-CTX plasma levels at baseline and fall-related fractures reported during a 1-year follow-up among individuals with established SCI. We recommend studies with larger SCI populations before further clinical implications can be drawn.

Fractures and musculoskeletal ailments in persons 20+ years after a traumatic spinal cord injury in Norway.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To gain insights into fracture rate and musculoskeletal ailments among Norwegians with a spinal cord injury (SCI) acquired more than 20 years ago. SETTINGS: Sunnaas Hospital, Nesoddtangen, Norway. METHODS: 165 persons with SCI were interviewed in 2004-2005 by questionnaires and clinical examination. Descriptive statistics and a logistic regression analysis were performed to identify variables associated with bone fractures and musculoskeletal ailments. RESULTS: Around half of the participants experienced a fracture after injury and excessive use of alcohol increased the odds (OR 0.09; CI 0.01-0.74) of suffering a post-injury fracture (p = 0.03). Sixty percent experienced shoulder ailments after the SCI and the use of orthosis to the knee and hip increased the odds (OR 4.4; CI 1.4-13) of experiencing shoulder ailment (p = 0.01). CONCLUSION: Around half of the 165 participants reported to have suffered a fracture and over 100 to experience musculoskeletal ailment 20 years after injury. We suggest that prevention strategies and symptom management must be embedded in follow-up visits after SCI.

Normalization of disrupted clock gene expression in males with tetraplegia: a crossover randomized placebo-controlled trial of melatonin supplementation.

STUDY DESIGN: Crossover double blind, randomized placebo-controlled trial. OBJECTIVES: Circadian oscillators are located both in the brain and in peripheral organs. Melatonin, the main brain-derived hormone governing circadian variations, is highly associated with daylight patterns. However, in subjects with tetraplegia the melatonin levels are blunted. Here we studied peripheral oscillators in peripheral blood mononuclear cells (PBMCs) in males with tetraplegia by examining how exogenous melatonin may influence the expression of clock gene mRNAs. SETTING: Sunnaas Rehabilitation Hospital, Nesoddtangen, Norway. METHODS: Six males with tetraplegia received 2 mg of melatonin or placebo 4 days before the study period. We also included six able-bodied men sleeping or kept awake during the night. Plasma samples were collected four times during a 24-h period. The mRNA expression levels of the clock genes PER1, PER2, BMAL1, and REV-ERBα were quantified in PBMCs using quantitative RT-PCR. RESULTS: The mRNA expression levels of PER-1 and -2 and REV-ERBα were increased at 04:00 h compared with the able-bodied controls (p < 0.05). Melatonin supplementation changed mRNA peak-time toward the time of supplementation. CONCLUSIONS: Several peripheral clock genes displayed distorted expression levels in tetraplegia. Supplementation with melatonin changed the mRNA expression levels of these genes toward those observed among able-bodied. SPONSORSHIP: Financial support was provided from the Throne Holst Foundation, Sunnaas Rehabilitation hospital and the University of Ferrara (FAR2016).

Retained differentiation capacity of human skeletal muscle satellite cells from spinal cord-injured individuals.

Despite the well-known role of satellite cells in skeletal muscle plasticity, the effect of spinal cord injury on their function in humans remains unknown. We determined whether spinal cord injury affects the intrinsic ability of satellite cells to differentiate and produce metabolically healthy myotubes. We obtained vastus lateralis biopsies from eight spinal cord-injured and six able-bodied individuals. Satellite cells were isolated, grown and differentiated in vitro. Gene expression was measured by quantitative PCR. Abundance of differentiation markers and regulatory proteins was determined by Western blotting. Protein synthesis and fatty acid oxidation were measured by radioactive tracer-based assays. Activated satellite cells (myoblasts) and differentiated myotubes derived from skeletal muscle of able-bodied and spinal cord-injured individuals expressed similar (P > 0.05) mRNA levels of myogenic regulatory factors. Myogenic differentiation factor 1 expression was higher in myoblasts from spinal cord-injured individuals. Desmin and myogenin protein content was increased upon differentiation in both groups, while myotubes from spinal cord-injured individuals contained more type I and II myosin heavy chain. Phosphorylated and total protein levels of Akt-mechanistic target of rapamycin and forkhead box protein O signalling axes and protein synthesis rate in myotubes were similar (P > 0.05) between groups. Additionally, fatty acid oxidation of myotubes from spinal cord-injured individuals was unchanged (P > 0.05) compared to able-bodied controls. Our results indicate that the intrinsic differentiation capacity of satellite cells and metabolic characteristics of myotubes are preserved following spinal cord injury. This may inform potential interventions targeting satellite cell activation to alleviate skeletal muscle atrophy.

MicroRNA-208b progressively declines after spinal cord injury in humans and is inversely related to myostatin expression.

The effects of long-term physical inactivity on the expression of microRNAs involved in the regulation of skeletal muscle mass in humans are largely unknown. MicroRNAs are short, noncoding RNAs that fine-tune target expression through mRNA degradation or by inhibiting protein translation. Intronic to the slow, type I, muscle fiber type genes MYH7 and MYH7b, microRNA-208b and microRNA-499-5p are thought to fine-tune the expression of genes important for muscle growth, such as myostatin. Spinal cord injured humans are characterized by both skeletal muscle atrophy and transformation toward fast-twitch, type II fibers. We determined the expression of microRNA-208b, microRNA-499-5p, and myostatin in human skeletal muscle after complete cervical spinal cord injury. We also determined whether these microRNAs altered myostatin expression in rodent skeletal muscle. A progressive decline in skeletal muscle microRNA-208b and microRNA-499-5p expression occurred in humans during the first year after spinal cord injury and with long-standing spinal cord injury. Expression of myostatin was inversely correlated with microRNA-208b and microRNA-499-5p in human skeletal muscle after spinal cord injury. Overexpression of microRNA-208b in intact mouse skeletal muscle decreased myostatin expression, whereas microRNA-499-5p was without effect. In conclusion, we provide evidence for an inverse relationship between expression of microRNA-208b and its previously validated target myostatin in humans with severe skeletal muscle atrophy. Moreover, we provide direct evidence that microRNA-208b overexpression decreases myostatin gene expression in intact rodent muscle. Our results implicate that microRNA-208b modulates myostatin expression and this may play a role in the regulation of skeletal muscle mass following spinal cord injury.

Reduced peak, but no diurnal variation, in thrombin generation upon melatonin supplementation in tetraplegia. A randomised, placebo-controlled study.

Tetraplegic patients have increased risk of venous thrombosis despite anti-thrombotic prophylaxis. Moreover, they have blunted plasma variations in melatonin and altered diurnal variation of several haemostatic markers, compared with able-bodied. However, whether healthy individuals and tetraplegic patients, with or without melatonin, display abnormalities in thrombin generation during a 24-hour (h) cycle, is unknown. We therefore used the Calibrated Automated Thrombogram (CAT) assay to examine diurnal variations and the possible role of melatonin in thrombin generation. Six men with long-standing complete tetraplegia were included in a randomised placebo-controlled cross-over study with melatonin supplementation (2 mg, 4 consecutive nights), whereas six healthy, able-bodied men served as controls. Ten plasma samples were collected frequently during a 24-h awake/sleep cycle. No significant diurnal variation of any of the measured CAT indices was detected in the three study groups. Whereas endogenous thrombin potential (ETP) was independent (p > 0.05) of whether the tetraplegic men received melatonin or placebo, melatonin decreased (p = 0.005) peak values in tetraplegia compared with those given placebo. Able-bodied men had lower (p = 0.019) ETP and Lag-Time (p = 0.018) compared with tetraplegics receiving placebo. Neither the Time-to-Peak nor the Start-Tail was affected (p > 0.05) by melatonin in tetraplegia. In conclusion, indices of thrombin generation are not subjected to diurnal variation in healthy able-bodied or tetraplegia, but peak thrombin generation is reduced in tetraplegic men receiving oral melatonin.

Altered content of AMP-activated protein kinase isoforms in skeletal muscle from spinal cord injured subjects.

AMP-activated protein kinase (AMPK) is a pivotal regulator of energy homeostasis. Although downstream targets of AMPK are widely characterized, the physiological factors governing isoform expression of this protein kinase are largely unknown. Nerve/contractile activity has a major impact on the metabolic phenotype of skeletal muscle, therefore likely to influence AMPK isoform expression. Spinal cord injury represents an extreme form of physical inactivity, with concomitant changes in skeletal muscle metabolism. We assessed the influence of longstanding and recent spinal cord injury on protein abundance of AMPK isoforms in human skeletal muscle. We also determined muscle fiber type as a marker of glycolytic or oxidative metabolism. In subjects with longstanding complete injury, protein abundance of the AMPKγ3 subunit, as well as myosin heavy chain (MHC) IIa and IIx, were increased, whereas abundance of the AMPKγ1 subunit and MHC I were decreased. Similarly, abundance of AMPKγ3 and MHC IIa proteins were increased, whereas AMPKα2, -ß1, and -γ1 subunits and MHC I abundance was decreased during the first year following injury, reflecting a more glycolytic phenotype of the skeletal muscle. However, in incomplete cervical lesions, partial recovery of muscle function attenuated the changes in the isoform profile of AMPK and MHC. Furthermore, exercise training (electrically stimulated leg cycling) partly normalized mRNA expression of AMPK isoforms. Thus, physical activity affects the relative expression of AMPK isoforms. In conclusion, skeletal muscle abundance of AMPK isoforms is related to physical activity and/or muscle fiber type. Thus, physical/neuromuscular activity is an important determinant of isoform abundance of AMPK and MCH. This further underscores the need for physical activity as part of a treatment regimen after spinal cord injury to maintain skeletal muscle metabolism.

Reduced antioxidant defense and increased oxidative stress in spinal cord injured patients.

OBJECTIVE: To determine the plasma and urine levels of antioxidants and oxidative stress biomarkers in subjects with spinal cord injury (SCI) the first year after injury. DESIGN: Descriptive 1-year follow-up study. SETTING: Rehabilitation and research center. PARTICIPANTS: SCI subjects (n=37; age range, 18-70 y) consecutively enrolled within the first month after injury. A healthy, able-bodied control group (n=346) was also included. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Blood and urine levels of antioxidants and oxidative stress biomarkers were measured at inclusion and after 3 and 12 months postinjury. RESULTS: One month after injury, the plasma antioxidants (total and oxidized glutathione and 6 different carotenoids and α-tocopherol) were reduced by 19% to 71% among the SCI subjects compared with the controls. The redox potential was reduced by 7% among the SCI subjects. The oxidative stress biomarker urinary 8-epi prostagladin F2α (PGF2α) increased to 161% in the SCI subjects compared with the controls. After 3 and 12 months, most of the antioxidant biomarkers were still significantly reduced compared with the controls, while urinary 8-epi PGF2α had increased to 208% compared with the controls. CONCLUSIONS: The levels of antioxidants were significantly lower, while the marker of oxidative stress was higher in the SCI subjects compared with the controls. This observation demonstrates that SCI patients experience increased oxidative stress and reduced antioxidant defense the first year after injury. Our findings warrant intervention studies where SCI patients receive dietary antioxidant support as part of their rehabilitation.

Influence of chronic and acute spinal cord injury on skeletal muscle Na+-K+-ATPase and phospholemman expression in humans.

Na(+)-K(+)-ATPase is an integral membrane protein crucial for the maintenance of ion homeostasis and skeletal muscle contractibility. Skeletal muscle Na(+)-K(+)-ATPase content displays remarkable plasticity in response to long-term increase in physiological demand, such as exercise training. However, the adaptations in Na(+)-K(+)-ATPase function in response to a suddenly decreased and/or habitually low level of physical activity, especially after a spinal cord injury (SCI), are incompletely known. We tested the hypothesis that skeletal muscle content of Na(+)-K(+)-ATPase and the associated regulatory proteins from the FXYD family is altered in SCI patients in a manner dependent on the severity of the spinal cord lesion and postinjury level of physical activity. Three different groups were studied: 1) six subjects with chronic complete cervical SCI, 2) seven subjects with acute, complete cervical SCI, and 3) six subjects with acute, incomplete cervical SCI. The individuals in groups 2 and 3 were studied at months 1, 3, and 12 postinjury, whereas individuals with chronic SCI were compared with an able-bodied control group. Chronic complete SCI was associated with a marked decrease in [(3)H]ouabain binding site concentration in skeletal muscle as well as reduced protein content of the α(1)-, α(2)-, and ß(1)-subunit of the Na(+)-K(+)-ATPase. In line with this finding, expression of the Na(+)-K(+)-ATPase α(1)- and α(2)-subunits progressively decreased during the first year after complete but not after incomplete SCI. The expression of the regulatory protein phospholemman (PLM or FXYD1) was attenuated after complete, but not incomplete, cervical SCI. In contrast, FXYD5 was substantially upregulated in patients with complete SCI. In conclusion, the severity of the spinal cord lesion and the level of postinjury physical activity in patients with SCI are important factors controlling the expression of Na(+)-K(+)-ATPase and its regulatory proteins PLM and FXYD5.

Differential expression of metabolic genes essential for glucose and lipid metabolism in skeletal muscle from spinal cord injured subjects.

Skeletal muscle plays an important role in the regulation of energy homeostasis; therefore, the ability of skeletal muscle to adapt and alter metabolic gene expression in response to changes in physiological demands is critical for energy balance. Individuals with cervical spinal cord lesions are characterized by tetraplegia, impaired thermoregulation, and altered skeletal muscle morphology. We characterized skeletal muscle metabolic gene expression patterns, as well as protein content, in these individuals to assess the impact of spinal cord injury on critical determinants of skeletal muscle metabolism. Our results demonstrate that mRNA levels and protein expression of skeletal muscle genes essential for glucose storage are reduced, whereas expression of glycolytic genes is reciprocally increased in individuals with spinal cord injury. Furthermore, expression of genes essential for lipid oxidation is coordinately reduced in spinal cord injured subjects, consistent with a marked reduction of mitochondrial proteins. Thus spinal cord injury resulted in a profound and tightly coordinated change in skeletal muscle metabolic gene expression program that is associated with the aberrant metabolic features of the tissue.

Melatonin stimulates release of tissue factor pathway inhibitor from the vascular endothelium.

We previously found an association between the circadian variation of free tissue factor pathway inhibitor (TFPI) and melatonin in able-bodied males and in men with complete cervical spinal cord injuries. We therefore examined whether melatonin modifies production and/or secretion of TFPI in endothelial cells. We sampled supernatants from cultures of primary human umbilical vein endothelial cells (HUVECs) and of human coronary artery endothelial cells (HCAECs), that had been exposed to varying doses (0-300 pg/ml) of melatonin for 0.5-24 h. We then measured the protein concentrations of free TFPI, tissue factor and plasminogen activator inhibitor type 1 (PAI-1). We also measured endothelial TFPI, tissue factor and PAI-1 transcripts using quantitative real-time PCR. Melatonin dose dependently increased free TFPI levels about 25-30-fold in supernatants of both HUVEC and HCAEC, and independent of incubation duration. In contrast, TF and PAI-1 remained unaltered upon increasing doses of melatonin. Neither TFPI mRNAs nor tissue factor mRNAs nor PAI-1-mRNAs were changed in cell cultures added melatonin. The ratio of free TFPI in cell supernatants to free TFPI in cell lysates about doubled upon addition of melatonin, indicating that melatonin increased release from intracellular storages of free TFPI or from membrane-bound free TFPI. Our data indicate that melatonin stimulates vascular endothelial cells to secrete TFPI without altering transcription of the TFPI gene. If melatonin increases TFPI release in a similar fashion in vivo as in vitro, this could have potential clinical implications in both prophylaxis and treatment of thromboembolic events.

[Complications of chronic spinal cord injury]. / Komplikasjoner etter kronisk ryggmargsskade.

BACKGROUND: A spinal cord injury changes body composition and metabolism over time. The main purpose of this article is to provide an overview of what is known about these changes and the consequences of those in the chronic phase, long after the acute injury. MATERIAL AND METHODS: The article is based on own research and clinical experience, as well as a non-systematic search in the PubMed database. RESULTS: The following has been documented for people with spinal cord injury: reduced bone and muscle mass, altered composition of muscle fibre, marked increase of body fat, decreased sensitivity to insulin and leptin and an increased activity in inflammatory signalling pathways. Changes are also demonstrated in hemostatic mechanisms and immune system. INTERPRETATION: Changes in metabolism and hormonal regulation in people with spinal cord injury, may increase the risk of osteoporosis, obesity, cardiovascular disease and type 2 diabetes. Changed body composition and inflammatory activity may contribute to the higher incidence of cardiovascular disease and diabetes/metabolic syndrome, although other important risk factors (such as obesity and high blood pressure) may be absent. It has not been documented that changes in haemostatic mechanisms and the immune system are associated with the increased incidence of thromboembolic complications, severe infections or certain types of cancer.