Administration of a selective retinoic acid receptor-γ agonist improves neuromuscular strength in a rodent model of volumetric muscle loss.

PURPOSE: Volumetric muscle loss is a uniquely challenging pathology that results in irrecoverable functional deficits. Furthermore, a breakthrough drug or bioactive factor has yet to be established that adequately improves repair of these severe skeletal muscle injuries. This study sought to assess the ability of an orally administered selective retinoic acid receptor-γ agonist, palovarotene, to improve recovery of neuromuscular strength in a rat model of volumetric muscle loss. METHODS: An irrecoverable, full thickness defect was created in the tibialis anterior muscle of Lewis rats and animals were survived for 4 weeks. Functional recovery of the tibialis anterior muscle was assessed in vivo via neural stimulation and determination of peak isometric torque. Histological staining was performed to qualitatively assess fibrous scarring of the defect site. RESULTS: Treatment with the selective retinoic acid receptor-γ agonist, palovarotene, resulted in a 38% improvement of peak isometric torque in volumetric muscle loss affected limbs after 4 weeks of healing compared to untreated controls. Additionally, preliminary histological assessment suggests that oral administration of palovarotene reduced fibrous scarring at the defect site. CONCLUSIONS: These results highlight the potential role of selective retinoic acid receptor-γ agonists in the design of regenerative medicine platforms to maximize skeletal muscle healing. Additional studies are needed to further elucidate cellular responses, optimize therapeutic delivery, and characterize synergistic potential with adjunct therapies.

Hematological and Hemodynamic Responses to Acute and Short-Term Creatine Nitrate Supplementation.

In a double-blind, crossover, randomized and placebo-controlled trial; 28 men and women ingested a placebo (PLA), 3 g of creatine nitrate (CNL), and 6 g of creatine nitrate (CNH) for 6 days. Participants repeated the experiment with the alternate supplements after a 7-day washout. Hemodynamic responses to a postural challenge, fasting blood samples, and bench press, leg press, and cycling time trial performance and recovery were assessed. Data were analyzed by univariate, multivariate, and repeated measures general linear models (GLM). No significant differences were found among treatments for hemodynamic responses, clinical blood markers or self-reported side effects. After 5 days of supplementation, one repetition maximum (1RM) bench press improved significantly for CNH (mean change, 95% CI; 6.1 [3.5, 8.7] kg) but not PLA (0.7 [-1.6, 3.0] kg or CNL (2.0 [-0.9, 4.9] kg, CNH, p = 0.01). CNH participants also tended to experience an attenuated loss in 1RM strength during the recovery performance tests following supplementation on day 5 (PLA: -9.3 [-13.5, -5.0], CNL: -9.3 [-13.5, -5.1], CNH: -3.9 [-6.6, -1.2] kg, p = 0.07). After 5 days, pre-supplementation 1RM leg press values increased significantly, only with CNH (24.7 [8.8, 40.6] kg, but not PLA (13.9 [-15.7, 43.5] or CNL (14.6 [-0.5, 29.7]). Further, post-supplementation 1RM leg press recovery did not decrease significantly for CNH (-13.3 [-31.9, 5.3], but did for PLA (-30.5 [-53.4, -7.7] and CNL (-29.0 [-49.5, -8.4]). CNL treatment promoted an increase in bench press repetitions at 70% of 1RM during recovery on day 5 (PLA: 0.4 [-0.8, 1.6], CNL: 0.9 [0.35, 1.5], CNH: 0.5 [-0.2, 0.3], p = 0.56), greater leg press endurance prior to supplementation on day 5 (PLA: -0.2 [-1.6, 1.2], CNL: 0.9 [0.2, 1.6], CNH: 0.2 [-0.5, 0.9], p = 0.25) and greater leg press endurance during recovery on day 5 (PLA: -0.03 [-1.2, 1.1], CNL: 1.1 [0.3, 1.9], CNH: 0.4 [-0.4, 1.2], p = 0.23). Cycling time trial performance (4 km) was not affected. Results indicate that creatine nitrate supplementation, up to a 6 g dose, for 6 days, appears to be safe and provide some ergogenic benefit.

Short-Term Effects of a Ready-to-Drink Pre-Workout Beverage on Exercise Performance and Recovery.

In a double-blind, randomized and crossover manner, 25 resistance-trained participants ingested a placebo (PLA) beverage containing 12 g of dextrose and a beverage (RTD) containing caffeine (200 mg), ß-alanine (2.1 g), arginine nitrate (1.3 g), niacin (65 mg), folic acid (325 mcg), and Vitamin B12 (45 mcg) for 7-days, separated by a 7-10-day. On day 1 and 6, participants donated a fasting blood sample and completed a side-effects questionnaire (SEQ), hemodynamic challenge test, 1-RM and muscular endurance tests (3 × 10 repetitions at 70% of 1-RM with the last set to failure on the bench press (BP) and leg press (LP)) followed by ingesting the assigned beverage. After 15 min, participants repeated the hemodynamic test, 1-RM tests, and performed a repetition to fatigue (RtF) test at 70% of 1-RM, followed by completing the SEQ. On day 2 and 7, participants donated a fasting blood sample, completed the SEQ, ingested the assigned beverage, rested 30 min, and performed a 4 km cycling time-trial (TT). Data were analyzed by univariate, multivariate, and repeated measures general linear models (GLM), adjusted for gender and relative caffeine intake. Data are presented as mean change (95% CI). An overall multivariate time × treatment interaction was observed on strength performance variables (p = 0.01). Acute RTD ingestion better maintained LP 1-RM (PLA: -0.285 (-0.49, -0.08); RTD: 0.23 (-0.50, 0.18) kg/kgFFM, p = 0.30); increased LP RtF (PLA: -2.60 (-6.8, 1.6); RTD: 4.00 (-0.2, 8.2) repetitions, p = 0.031); increased BP lifting volume (PLA: 0.001 (-0.13, 0.16); RTD: 0.03 (0.02, 0.04) kg/kgFFM, p = 0.007); and, increased total lifting volume (PLA: -13.12 (-36.9, 10.5); RTD: 21.06 (-2.7, 44.8) kg/kgFFM, p = 0.046). Short-term RTD ingestion maintained baseline LP 1-RM (PLA: -0.412 (-0.08, -0.07); RTD: 0.16 (-0.50, 0.18) kg/kgFFM, p = 0.30); LP RtF (PLA: 0.12 (-3.0, 3.2); RTD: 3.6 (0.5, 6.7) repetitions, p = 0.116); and, LP lifting volume (PLA: 3.64 (-8.8, 16.1); RTD: 16.25 (3.8, 28.7) kg/kgFFM, p = 0.157) to a greater degree than PLA. No significant differences were observed between treatments in cycling TT performance, hemodynamic assessment, fasting blood panels, or self-reported side effects.

Aldosterone-mediated apical targeting of ENaC subunits is blunted in rats with streptozotocin-induced diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) is associated with a significant polyuria and natriuesis as well as increased plasma aldosterone and anti-diuretic hormone arginine vasopressin (AVP). This study aimed to determine whether diabetic kidneys compensate for the urinary sodium and water losses by increasing apical targeting of epithelial sodium channel (ENaC) subunits and aquaporin-2 (AQP2) in the collecting duct, in addition to the previously observed changes in ENaC subunit protein expression in different kidney zones. METHODS: Female rats were investigated 2 weeks after induction of DM by streptozotocin administration. Kidneys were examined by immunohistochemisty and semiquantitative immunoblotting. RESULTS: We demonstrated that the protein expression of renal AQP2, Ser-256 phosphorylated AQP2, AQP3, beta- and gamma-ENaC (but not alpha-ENaC) increased consistently with an increased AVP response. In contrast, there were no significant changes in the relative apical targeting of beta-, gamma- and alpha-ENaC, and the shift in the molecular weight of gamma-ENaC from 85 kDa to 70 kDa was not observed despite increased plasma aldosterone levels. These results were supported by changes in the functional data showing increased solute-free water reabsorption, increased fractional excretion of sodium and an unchanged ratio of potassium to sodium in the urine. CONCLUSIONS: The data demonstrate that diabetic kidneys have a reduced sensitivity to the anti-natriuretic action of elevated plasma aldosterone levels with no relative increase in ENaC subunit apical targeting, whereas there is increased expression of beta- and gamma-ENaC, which alone may play a role in the increased sodium reabsorption in the kidney in DM.