Testosterone and long pulse width stimulation (TLPS) for denervated muscles after spinal cord injury: a study protocol of randomised clinical trial.

INTRODUCTION: Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate denervated muscles and to restore muscle size in denervated people with spinal cord injury (SCI). We will determine if testosterone treatment (TT)+LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in persons with SCI with denervation. We hypothesise that the 1-year TT+LPWS will upregulate protein synthesis pathways, downregulate protein degradation pathways and increase overall mitochondrial health. METHODS AND ANALYSIS: Twenty-four male participants (aged 18-70 years with chronic SCI) with denervation of both knee extensor muscles and tolerance to the LPWS paradigm will be randomised into either TT+neuromuscular electrical stimulation via telehealth or TT+LPWS. The training sessions will be twice weekly for 1 year. Measurements will be conducted 1 week prior training (baseline; week 0), 6 months following training (postintervention 1) and 1 week after the end of 1 year of training (postintervention 2). Measurements will include body composition assessment using anthropometry, dual X-ray absorptiometry and MRI to measure size of different muscle groups. Metabolic profile will include measuring of basal metabolic rate, followed by blood drawn to measure fasting biomarkers similar to hemoglobin A1c, lipid panels, C reactive protein, interleukin-6 and free fatty acids and then intravenous glucose tolerance test to test for insulin sensitivity and glucose effectiveness. Finally, muscle biopsy will be captured to measure protein expression and intracellular signalling; and mitochondrial electron transport chain function. The participants will fill out 3 days dietary record to monitor their energy intake on a weekly basis. ETHICS AND DISSEMINATION: The study was approved by Institutional Review Board of the McGuire Research Institute (ID # 02189). Dissemination plans will include the Veteran Health Administration and its practitioners, the national SCI/D services office, the general healthcare community and the veteran population, as well as the entire SCI community via submitting quarterly letters or peer-review articles. TRIAL REGISTRATION NUMBER: NCT03345576.

Hepatic Portal Venous Gas: A Potentially Lethal Sign Demanding Urgent Management.

BACKGROUND Hepatic portal venous gas is a rare and concerning finding occasionally seen on computed tomography (CT) scans, and must be emergently managed, often in the operating room. This condition can present in conjunction with bowel distension, pneumatosis intestinalis, and intestinal ischemia, so care must be taken to examine the imaging closely so as not to miss this dire condition. This report summarizes our experience with a patient who had this problem and how urgent management prevented a lethal outcome. CASE REPORT The patient was a 77-year-old morbidly obese man whose complicated hospital course began with admission for abdominal pain evaluation. This led to a flexible sigmoidoscopy for concerning CT findings suggestive of colitis or malignancy, leading to a perforation at the anterior wall of the sigmoid-rectal junction. Urgent sigmoid colectomy and Hartmann's procedure were performed along with pelvic drainage. Blood cultures returned positive for Klebsiella. After 10 days, the patient decompensated, and a CT scan showed pneumatosis intestinalis, hepatic portal venous gas, and diffuse small bowel distension. Rectal stump dehiscence had occurred; therefore, 2 repeat abdominal wash-outs were performed with aggressive intensive care. The patient eventually stabilized and was ultimately discharged to a skilled nursing facility 32 days later. CONCLUSIONS This case illustrates the importance of prompt imaging, medical management, and, if necessary, surgical exploration in the patient with bowel distension and hepatic portal venous gas on a CT scan. Although uncommon, this finding indicates a potentially poor prognosis and must be addressed emergently to prevent bowel ischemia from progressing in patients with underlying abdominal pathology.

Assessment of mitochondrial respiratory capacity using minimally invasive and noninvasive techniques in persons with spinal cord injury.

PURPOSE: Muscle biopsies are the gold standard to assess mitochondrial respiration; however, biopsies are not always a feasible approach in persons with spinal cord injury (SCI). Peripheral blood mononuclear cells (PBMCs) and near-infrared spectroscopy (NIRS) may alternatively be predictive of mitochondrial respiration. The purpose of the study was to evaluate whether mitochondrial respiration of PBMCs and NIRS are predictive of respiration of permeabilized muscle fibers after SCI. METHODS: Twenty-two individuals with chronic complete and incomplete motor SCI between 18-65 years old were recruited to participate in the current trial. Using high-resolution respirometry, mitochondrial respiratory capacity was measured for PBMCs and muscle fibers of the vastus lateralis oxidizing complex I, II, and IV substrates. NIRS was used to assess mitochondrial capacity of the vastus lateralis with serial cuff occlusions and electrical stimulation. RESULTS: Positive relationships were observed between PBMC and permeabilized muscle fibers for mitochondrial complex IV (r = 0.86, P < 0.0001). Bland-Altman displayed agreement for complex IV (MD = 0.18, LOA = -0.86 to 1.21), between PBMCs and permeabilized muscles fibers. No significant relationships were observed between NIRS mitochondrial capacity and respiration in permeabilized muscle fibers. CONCLUSIONS: This is the first study to explore and support the agreement of less invasive clinical techniques for assessing mitochondrial respiratory capacity in individuals with SCI. The findings will assist in the application of PBMCs as a viable alternative for assessing mitochondrial health in persons with SCI in future clinical studies.

Neuromuscular electrical stimulation resistance training enhances oxygen uptake and ventilatory efficiency independent of mitochondrial complexes after spinal cord injury: a randomized clinical trial.

The purpose of the study was to determine whether neuromuscular electrical stimulation resistance training (NMES-RT)-evoked muscle hypertrophy is accompanied by increased V̇o2 peak, ventilatory efficiency, and mitochondrial respiration in individuals with chronic spinal cord injury (SCI). Thirty-three men and women with chronic, predominantly traumatic SCI were randomized to either NMES-RT (n = 20) or passive movement training (PMT; n = 13). Functional electrical stimulation-lower extremity cycling (FES-LEC) was used to test the leg V̇o2 peak, V̇E/V̇co2 ratio, and substrate utilization pre- and postintervention. Magnetic resonance imaging was used to measure muscle cross-sectional area (CSA). Finally, muscle biopsy was performed to measure mitochondrial complexes and respiration. The NMES-RT group showed a significant increase in postintervention V̇o2 peak compared with baseline (ΔV̇o2 = 14%, P < 0.01) with no changes in the PMT group (ΔV̇o2 = 1.6%, P = 0.47). Similarly, thigh (ΔCSAthigh = 19%) and knee extensor (ΔCSAknee = 30.4%, P < 0.01) CSAs increased following NMES-RT but not after PMT. The changes in thigh and knee extensor muscle CSAs were positively related with the change in V̇o2 peak. Neither NMES-RT nor PMT changed mitochondrial complex tissue levels; however, changes in peak V̇o2 were related to complex I. In conclusion, in persons with SCI, NMES-RT-induced skeletal muscle hypertrophy was accompanied by increased peak V̇o2 consumption which may partially be explained by enhanced activity of mitochondrial complex I.NEW & NOTEWORTHY Leg oxygen uptake (V̇o2) and ventilatory efficiency (V̇E/V̇co2 ratio) were measured during functional electrical stimulation cycling testing following 12-16 wk of either electrically evoked resistance training or passive movement training, and the respiration of mitochondrial complexes. Resistance training increased thigh muscle area and leg V̇o2 peak but decreased V̇E/V̇co2 ratio without changes in mitochondrial complex levels. Leg V̇o2 peak was associated with muscle hypertrophy and mitochondrial respiration of complex I following training.

Sixteen weeks of testosterone with or without evoked resistance training on protein expression, fiber hypertrophy and mitochondrial health after spinal cord injury.

We investigated the effects of testosterone replacement therapy (TRT) with and without evoked resistance training (RT) on protein expression of key metabolic and hypertrophy regulators, muscle fiber cross-sectional area (CSA), and markers of mitochondrial health after spinal cord injury (SCI). Twenty-two men with chronic motor complete SCI were randomly assigned to either TRT + RT (n = 11) or TRT (n = 11) for 16 wk. TRT + RT men underwent twice weekly progressive RT using electrical stimulation with ankle weights. TRT was administered via testosterone patches (2-6 mg/day). Muscle biopsies were obtained before and after 16 wk from the right vastus lateralis. Expression of proteins associated with oxidative muscles and mechanical loading (PGC-1α and FAK), muscle hypertrophy (total and phosphorylated Akt, total and phosphorylated mTOR), and cellular metabolism (total and phosphorylated AMPK and GLUT4) were evaluated. Immunohistochemistry analysis was performed to measure fiber CSA and succinate dehydrogenase (SDH) activity as well as mitochondrial citrate synthase (CS) activity and complex III (CIII) activities. TRT + RT demonstrated a robust 27.5% increase in average fiber CSA compared with a -9% decrease following TRT only (P = 0.01). GLUT4 protein expression was elevated in the TRT + RT group compared with TRT only (P = 0.005). Total Akt (P = 0.06) and phosphorylated Akt Ser389 (P = 0.049) were also elevated in the TRT + RT group. Mitochondrial activity of SDH (P = 0.03) and CS (P = 0.006) increased in the TRT + RT group, with no changes in the TRT-only group. Sixteen weeks of TRT with RT resulted in fiber hypertrophy and beneficial changes in markers of skeletal muscle health and function.NEW & NOTEWORTHY Fiber cross-sectional area (CSA), protein expression, mitochondrial citrate synthase (CS), and succinate dehydrogenase (SDH) were measured following 16 wk of low-dose testosterone replacement therapy (TRT) with and without electrically evoked resistance training (RT) in men with spinal cord injury (SCI). Fiber CSA and protein expression of total GLUT4, total Akt, and phosphorylated Akt increased following TRT + RT but not in the TRT-only group. Mitochondrial CS and SDH increased after TRT + RT but not in TRT-only group.

Skeletal muscle hypertrophy and attenuation of cardio-metabolic risk factors (SHARC) using functional electrical stimulation-lower extremity cycling in persons with spinal cord injury: study protocol for a randomized clinical trial.

BACKGROUND: Persons with spinal cord injury (SCI) are at heightened risks of developing unfavorable cardiometabolic consequences due to physical inactivity. Functional electrical stimulation (FES) and surface neuromuscular electrical stimulation (NMES)-resistance training (RT) have emerged as effective rehabilitation methods that can exercise muscles below the level of injury and attenuate cardio-metabolic risk factors. Our aims are to determine the impact of 12 weeks of NMES + 12 weeks of FES-lower extremity cycling (LEC) compared to 12 weeks of passive movement + 12 weeks of FES-LEC on: (1) oxygen uptake (VO2), insulin sensitivity, and glucose disposal in adults with SCI; (2) skeletal muscle size, intramuscular fat (IMF), and visceral adipose tissue (VAT); and (3) protein expression of energy metabolism, protein molecules involved in insulin signaling, muscle hypertrophy, and oxygen uptake and electron transport chain (ETC) activities. METHODS/DESIGN: Forty-eight persons aged 18-65 years with chronic (> 1 year) SCI/D (AIS A-C) at the C5-L2 levels, equally sub-grouped by cervical or sub-cervical injury levels and time since injury, will be randomized into either the NMES + FES group or Passive + FES (control group). The NMES + FES group will undergo 12 weeks of evoked RT using twice-weekly NMES and ankle weights followed by twice-weekly progressive FES-LEC for an additional 12 weeks. The control group will undergo 12 weeks of passive movement followed by 12 weeks of progressive FES-LEC. Measurements will be performed at baseline (B; week 0), post-intervention 1 (P1; week 13), and post-intervention 2 (P2; week 25), and will include: VO2 measurements, insulin sensitivity, and glucose effectiveness using intravenous glucose tolerance test; magnetic resonance imaging to measure muscle, IMF, and VAT areas; muscle biopsy to measure protein expression and intracellular signaling; and mitochondrial ETC function. DISCUSSION: Training through NMES + RT may evoke muscle hypertrophy and positively impact oxygen uptake, insulin sensitivity, and glucose effectiveness. This may result in beneficial outcomes on metabolic activity, body composition profile, mitochondrial ETC, and intracellular signaling related to insulin action and muscle hypertrophy. In the future, NMES-RT may be added to FES-LEC to improve the workloads achieved in the rehabilitation of persons with SCI and further decrease muscle wasting and cardio-metabolic risks. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02660073 . Registered on 21 Jan 2016.