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.

Visceral Adiposity, Inflammation, and Testosterone Predict Skeletal Muscle Mitochondrial Mass and Activity in Chronic Spinal Cord Injury.

BACKGROUND: Mitochondrial health is an important predictor of several health-related comorbidities including obesity, type 2 diabetes mellitus, and cardiovascular disease. In persons with spinal cord injury (SCI), mitochondrial health has been linked to several important body composition and metabolic parameters. However, the complex interplay of how mitochondrial health is affected has yet to be determined in this population. OBJECTIVE: In this study, we examined the contribution of visceral adiposity, inflammatory biomarkers, testosterone and circulating serum growth factors as predictors of mitochondrial health in persons with chronic SCI. PARTICIPANTS: Thirty-three individuals with chronic SCI (n = 27 Males, n = 6 Females, age: 40 ± 13.26 years, level of injury: C4-L1, BMI: 23 ± 5.57) participated in this cross-sectional study. METHODS: Visceral adipose tissue (VAT) was measured via magnetic resonance imaging (MRI). After an overnight fast, serum testosterone, inflammatory biomarkers [interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), c-reactive protein (CRP)], and anabolic growth factors [insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3)] were measured. Skeletal muscle biopsies were obtained from the vastus lateralis muscle to measure citrate synthase (CS) and Complex III activity. Regression analyses were used to examine predictors of mitochondrial mass and activity. RESULTS: CS activity was negatively associated with VAT (r 2 = 0.360, p < 0.001), CRP (r 2 = 0.168, p = 0.047), and positively associated with testosterone (r 2 = 0.145, p = 0.042). Complex III activity was negatively associated with VAT relative to total lean mass (VAT:TLM) (r 2 = 0.169, p = 0.033), trended for CRP (r 2 = 0.142, p = 0.069), and positively associated with testosterone (r 2 = 0.224, p = 0.010). Multiple regression showed CS activity was significantly associated with VAT + CRP (r 2 = 0.412, p = 0.008) and VAT + Testosterone (r 2 = 0.433, p = 0.001). Complex III activity was significantly associated with VAT relative to total trunk cross-sectional area (CSA) + CRP (VAT:total trunk CSA + CRP; r 2 = 0.286, p = 0.048) and VAT + Testosterone (r 2 = 0.277, p = 0.024). CONCLUSION: Increased visceral adiposity and associated inflammatory signaling (CRP) along with reduced testosterone levels predict mitochondrial dysfunction following SCI. Specifically, lower VATCSA and higher testosterone levels or lower VATCSA and lower CRP levels positively predict mitochondrial mass and enzyme activity in persons with chronic SCI. Future research should investigate the efficacy of diet, exercise, and potentially testosterone replacement therapy on enhancing mitochondrial health in chronic SCI. CLINICAL TRIAL REGISTRATION: [www.ClinicalTrials.gov], identifier: [NCT02660073].

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.

Organic solute carrier 22 (SLC22) family: Potential for interactions with food, herbal/dietary supplements, endogenous compounds, and drugs.

Many drugs, hormones, components of herbal medicines, environmental pesticides and toxins are Solute Carrier family 22 (SLC22) substrates. The last twenty years has seen great progress in determining SLC22 tissue expression profiles, membrane localization, energetics, substrate profiles and biopharmaceutical significance. However, much still remains to be answered in terms of SLC22 family member's roles in 'normal' physiology as compared to pathophysiological states, as well as in drug interactions that impact pharmacokinetics, efficacy and toxicity. This review begins with a brief synopsis of SLC22 family discovery, function and tissue expression. Subsequent sections provide examples establishing a role for SLC22 transporters in food-drug, herbal supplement-drug, endogenous substrate-drug and drug-drug interactions.