Subcutaneous injection of adipose stromal cell-secretome improves renal function and reduces inflammation in established acute kidney injury.

BACKGROUND: Adipose stromal cells (ASC) are a form of mesenchymal stromal cells that elicit effects primarily via secreted factors, which may have advantages for the treatment of injury or disease. Several previous studies have demonstrated a protective role for MSC/ASC on mitigating acute kidney injury but whether ASC derived factors could hasten recovery from established injury has not been evaluated. METHODS: We generated a concentrated secretome (CS) of human ASC under well-defined conditions and evaluated its ability to improve the recovery of renal function in a preclinical model of acute kidney injury (AKI) in rats. 24 h following bilateral ischemia/reperfusion (I/R), rats were randomized following determination of plasma creatinine into groups receiving vehicle -control or ASC-CS treatment by subcutaneous injection (2 mg protein/kg) and monitored for evaluation of renal function, structure and inflammation. RESULTS: Renal function, assessed by plasma creatinine levels, recovered faster in ASC-CS treated rats vs vehicle. The most prominent difference between the ASC-CS treated vs vehicle was observed in rats with the most severe degree of initial injury (Pcr > 3.0 mg/dl 24 h post I/R), whereas rats with less severe injury (Pcr < 2.9 mg/dl) recovered quickly regardless of treatment. The quicker recovery of ASC-treated rats with severe injury was associated with less tissue damage, inflammation, and lower plasma angiopoietin 2. In vitro, ASC-CS attenuated the activation of the Th17 phenotype in lymphocytes isolated from injured kidneys. CONCLUSIONS: Taken together, these data suggest that ASC-CS represents a potent therapeutic option to improve established AKI.

Effects of home-based leg heat therapy on walking performance in patients with symptomatic peripheral artery disease: a pilot randomized trial.

Few noninvasive therapies currently exist to improve functional capacity in people with lower extremity peripheral artery disease (PAD). The goal of the present study was to test the hypothesis that unsupervised, home-based leg heat therapy (HT) using water-circulating trousers perfused with warm water would improve walking performance in patients with PAD. Patients with symptomatic PAD were randomized into either leg HT (n = 18) or a sham treatment (n = 16). Patients were provided with water-circulating trousers and a portable pump and were asked to apply the therapy daily (7 days/wk, 90 min/session) for 8 wk. The primary study outcome was the change from baseline in 6-min walk distance at 8-wk follow-up. Secondary outcomes included the claudication onset-time, peak walking time, peak pulmonary oxygen consumption and peak blood pressure during a graded treadmill test, resting blood pressure, the ankle-brachial index, postocclusive reactive hyperemia in the calf, cutaneous microvascular reactivity, and perceived quality of life. Of the 34 participants randomized, 29 completed the 8-wk follow-up. The change in 6-min walk distance at the 8-wk follow-up was significantly higher (P = 0.029) in the group exposed to HT than in the sham-treated group (Sham: median: -0.9; 25%, 75% percentiles: -5.8, 14.3; HT: median: 21.3; 25%, 75% percentiles: 10.1, 42.4, P = 0.029). There were no significant differences in secondary outcomes between the HT and sham group at 8-wk follow-up. The results of this pilot study indicate that unsupervised, home-based leg HT is safe, well-tolerated, and elicits a clinically meaningful improvement in walking tolerance in patients with symptomatic PAD.NEW & NOTEWORTHY This is the first sham-controlled trial to examine the effects of home-based leg heat therapy (HT) on walking performance in patients with peripheral artery disease (PAD). We demonstrate that unsupervised HT using water-circulating trousers is safe, well-tolerated, and elicits meaningful changes in walking ability in patients with symptomatic PAD. This home-based treatment option is practical, painless, and may be a feasible adjunctive therapy to counteract the decline in lower extremity physical function in patients with PAD.

Kidney injury risk during prolonged exposure to current and projected wet bulb temperatures occurring during extreme heat events in healthy young men.

Wet bulb temperatures (Twet) during extreme heat events are commonly 31°C. Recent predictions indicate that Twet will approach or exceed 34°C. Epidemiological data indicate that exposure to extreme heat events increases kidney injury risk. We tested the hypothesis that kidney injury risk is elevated to a greater extent during prolonged exposure to Twet = 34°C compared with Twet = 31°C. Fifteen healthy men rested for 8 h in Twet = 31 (0)°C and Twet = 34 (0)°C. Insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2), and thioredoxin 1 (TRX-1) were measured from urine samples. The primary outcome was the product of IGFBP7 and TIMP-2 ([IGFBP7·TIMP-2]), which provided an index of kidney injury risk. Plasma interleukin-17a (IL-17a) was also measured. Data are presented at preexposure and after 8 h of exposure and as mean (SD) change from preexposure. The increase in [IGFBP7·TIMP-2] was markedly greater at 8 h in the 34°C [+26.9 (27.1) (ng/mL)2/1,000) compared with the 31°C [+6.2 (6.5) (ng/mL)2/1,000] trial (P < 0.01). Urine TRX-1, a marker of renal oxidative stress, was higher at 8 h in the 34°C [+77.6 (47.5) ng/min] compared with the 31°C [+16.2 (25.1) ng/min] trial (P < 0.01). Plasma IL-17a, an inflammatory marker, was elevated at 8 h in the 34°C [+199.3 (90.0) fg/dL; P < 0.01] compared with the 31°C [+9.0 (95.7) fg/dL] trial. Kidney injury risk is exacerbated during prolonged resting exposures to Twet experienced during future extreme heat events (34°C) compared with that experienced currently (31°C), likely because of oxidative stress and inflammatory processes.NEW AND NOTEWORTHY We have demonstrated that kidney injury risk is increased when men are exposed over an 8-h period to a wet bulb temperature of 31°C and exacerbated at a wet bulb temperature of 34°C. Importantly, these heat stress conditions parallel those that are encountered during current (31°C) and future (34°C) extreme heat events. The kidney injury biomarker analyses indicate both the proximal and distal tubules as the locations of potential renal injury and that the injury is likely due to oxidative stress and inflammation.

Acute effects of leg heat therapy on walking performance and cardiovascular and inflammatory responses to exercise in patients with peripheral artery disease.

Lower-extremity peripheral artery disease (PAD) is associated with increased risk of cardiovascular events and impaired exercise tolerance. We have previously reported that leg heat therapy (HT) applied using liquid-circulating trousers perfused with warm water increases leg blood flow and reduces blood pressure (BP) and the circulating levels of endothelin-1 (ET-1) in patients with symptomatic PAD. In this sham-controlled, randomized, crossover study, sixteen patients with symptomatic PAD (age 65 ± 5.7 years and ankle-brachial index: 0.69 ± 0.1) underwent a single 90-min session of HT or a sham treatment prior to a symptom-limited, graded cardiopulmonary exercise test on the treadmill. The primary outcome was the peak walking time (PWT) during the exercise test. Secondary outcomes included the claudication onset time (COT), resting and exercise BP, calf muscle oxygenation, pulmonary oxygen uptake (V̇O2 ), and plasma levels of ET-1, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Systolic, but not diastolic BP, was significantly lower (~7 mmHg, p < .05) during HT when compared to the sham treatment. There was also a trend for lower SBP throughout the exercise and the recovery period following HT (p = .057). While COT did not differ between treatments (p = .77), PWT tended to increase following HT (CON: 911 ± 69 s, HT: 954 ± 77 s, p = .059). Post-exercise plasma levels of ET-1 were also lower in the HT session (CON: 2.0 ± 0.1, HT: 1.7 ± 0.1, p = .02). Calf muscle oxygenation, V̇O2 , COT, IL-6, and TNF-α did not differ between treatments. A single session of leg HT lowers BP and post-exercise circulating levels of ET-1 and may enhance treadmill walking performance in symptomatic PAD patients.

Leg heat therapy improves perceived physical function but does not enhance walking capacity or vascular function in patients with peripheral artery disease.

A single session of leg heat therapy (HT) has been shown to elicit increases in leg blood flow and reduce blood pressure (BP) and the circulating levels of endothelin-1 (ET-1) in patients with symptomatic peripheral artery disease (PAD). We assessed whether 6 wk of supervised leg HT (3 times/wk) with water-circulating trousers perfused with water at 48°C improved 6-min walk distance in individuals with PAD compared with a sham treatment. Secondary outcomes included the assessment of leg vascular function, BP, quality of life, and serum ET-1 and nitrite plus nitrate (NOx) levels. Of 32 PAD patients randomized, 30 [age: 68 ± 8 yr; ankle-brachial index (ABI): 0.6 ± 0.1] completed the 3- and 6-wk follow-ups. Participants completed 98.7% of the treatment sessions. Compared with the sham treatment, exposure to HT did not improve 6-min walk distance, BP, popliteal artery reactive hyperemia, cutaneous microvascular reactivity, resting ABI, or serum NOx levels. The change from baseline to 6 wk in scores of the physical functioning subscale of the 36-item Short Form Health Survey was significantly higher in the HT group (control -6.9 ± 10 vs. HT 6.8 ± 15; 95% confidence interval: 2.5-24.3, P = 0.017). Similarly, the change in ET-1 levels after 6 wk was different between groups, with the HT group experiencing a 0.4 pg/mL decrease (95% confidence interval: -0.8-0.0, P = 0.03). These preliminary results indicate that leg HT may improve perceived physical function in symptomatic PAD patients. Additional, larger studies are needed to confirm these findings and determine the optimal treatment regimen for symptomatic PAD patients.NEW & NOTEWORTHY This is the first sham-controlled study to investigate the effects of leg heat therapy (HT) on walking performance, vascular function, and quality of life in patients with peripheral artery disease (PAD). Adherence to HT was high, and the treatment was well tolerated. Our findings revealed that HT applied with water-circulating trousers evokes a clinically meaningful increase in perceived physical function and reduces the serum concentration of the potent vasoconstrictor endothelin-1 in patients with PAD.

Local Heat Therapy to Accelerate Recovery After Exercise-Induced Muscle Damage.

The prolonged impairment in muscle strength, power, and fatigue resistance after eccentric exercise has been ascribed to a plethora of mechanisms, including delayed muscle refueling and microvascular and mitochondrial dysfunction. This review explores the hypothesis that local heat therapy hastens functional recovery after strenuous eccentric exercise by facilitating glycogen resynthesis, reversing vascular derangements, augmenting mitochondrial function, and stimulating muscle protein synthesis.

Skeletal muscle adaptations to heat therapy.

The therapeutic effects of heat have been harnessed for centuries to treat skeletal muscle disorders and other pathologies. However, the fundamental mechanisms underlying the well-documented clinical benefits associated with heat therapy (HT) remain poorly defined. Foundational studies in cultured skeletal muscle and endothelial cells, as well as in rodents, revealed that episodic exposure to heat stress activates a number of intracellular signaling networks and promotes skeletal muscle remodeling. Renewed interest in the physiology of HT in recent years has provided greater understanding of the signals and molecular players involved in the skeletal muscle adaptations to episodic exposures to HT. It is increasingly clear that heat stress promotes signaling mechanisms involved in angiogenesis, muscle hypertrophy, mitochondrial biogenesis, and glucose metabolism through not only elevations in tissue temperature but also other perturbations, including increased intramyocellular calcium and enhanced energy turnover. The few available translational studies seem to indicate that the earlier observations in rodents also apply to human skeletal muscle. Indeed, recent findings revealed that both local and whole-body HT may promote capillary growth, enhance mitochondrial content and function, improve insulin sensitivity and attenuate disuse-induced muscle wasting. This accumulating body of work implies that HT may be a practical treatment to combat skeletal abnormalities in individuals with chronic disease who are unwilling or cannot participate in traditional exercise-training regimens.

Effect of Acute Bouts of Volume-Matched High-Intensity Resistance Training Protocols on Blood Glucose Levels.

Monroe, JC, Naugle, KM, and Naugle, KE. Effect of acute bouts of volume-matched high-intensity resistance training protocols on blood glucose levels. J Strength Cond Res 34(2): 445-450, 2020-Resistance exercise has the capability to alter glucose metabolism in healthy adults; however, to what extent single sessions of varying intensities of resistance exercise affect capillary glucose levels is not completely understood. The purpose of this study was to compare the effect of different resistance training intensities on capillary blood glucose levels in healthy adults. Thirteen resistance-trained men (age 24.4 ± 2.7 years) participated in an evaluation and 2 separate experimental resistance training sessions. The experimental sessions were a high-intensity resistance training session (HT) consisting of 7 sets of 3 repetitions at 90% of the participant's estimated 1 repetition maximum (e1RM), and a moderate-/high-intensity resistance training session (MT) consisting of 3 sets of 9 repetitions at 70% of the participant's e1RM. At least 7 days separated the completion of each session. Four glucose readings during each session were recorded using a capillary glucometer: G1 (baseline); G2 (pre-exercise); G3 (after exercise); and G4 (10 minutes after exercise). Results were analyzed using repeated-measures analysis of variances. Analysis revealed a significant decrease in blood glucose levels between G2 and G3, and G2 and G4 in both the HT and MT experimental sessions (p = 0.045). In addition, there was a significant difference in the magnitude of change in glucose levels from G2 to G3 between HT and MT (HT = -38.2 ± 5.3% SE, p = 0.042, MT = -22.2 ± 5.9% SE). Although both of the acute resistance exercise protocols decreased blood glucose levels in healthy men, a greater decrease in blood glucose levels from pre-exercise to post-exercise was observed in HT group compared with MT group.