l-Leucine Increases Skeletal Muscle IGF-1 but Does Not Differentially Increase Akt/mTORC1 Signaling and Serum IGF-1 Compared to Ursolic Acid in Response to Resistance Exercise in Resistance-Trained Men

Objective: Ursolic acid administration following resistance exercise increases mammalian target of rapamycin complex 1 (mTORC1) activity and skeletal muscle IGF-1 concentration in murines in a manner similar to l-leucine yet remains unexamined in humans. This study examined serum and skeletal muscle insulin-like growth factor-1 (IGF-1) and Akt/mTORC1 signaling activity following ingestion of either ursolic acid or l-leucine immediately after resistance exercise.

Methods: Nine resistance-trained men performed 3 lower-body resistance exercise sessions involving 4 sets of 8–10 repetitions at 75%–80% one repetition maximum (1-RM) on the angled leg press and knee extension exercises. Immediately following each session, participants orally ingested 3 g cellulose placebo (PLC), l-leucine (LEU), or ursolic acid (UA). Blood samples were obtained pre-exercise and at 0.5, 2, and 6 hours postexercise. Muscle biopsies were obtained pre-exercise and at 2 and 6 hours postexercise.

Results: Plasma leucine increased in LEU at 2 hours postexercise compared to PLC (p = 0.04). Plasma ursolic acid increased in UA at 2 h and 6 hours postexercise compared to PLC and LEU (p < 0.003). No significant differences were observed for serum insulin (p = 0.98) and IGF-1 (p = 0.99) or skeletal muscle IGF-1 receptor (IGF-1R; p = 0.84), Akt (p = 0.55), mTOR (p = 0.09), and p70S6K (p = 0.98). Skeletal muscle IGF-1 was significantly increased in LEU at 2 hours postexercise (p = 0.03) and 6 hours postexercise (p = 0.04) compared to PLC and UA.

Conclusion: Three grams of l-leucine and ursolic acid had no effect on Akt/mTORC1 signaling or serum insulin or IGF-1; however, l-leucine increased skeletal muscle IGF-1 concentration in resistance-trained men.     

Mutations in TIMM50 cause severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology

3‐Methylglutaconic aciduria (3‐MGA‐uria) syndromes comprise a heterogeneous group of diseases associated with mitochondrial membrane defects. Whole‐exome sequencing identified compound heterozygous mutations in TIMM50 (c.[341 G>A];[805 G>A]) in a boy with West syndrome, optic atrophy, neutropenia, cardiomyopathy, Leigh syndrome, and persistent 3‐MGA‐uria. A comprehensive analysis of the mitochondrial function was performed in fibroblasts of the patient to elucidate the molecular basis of the disease. TIMM50 protein was severely reduced in the patient fibroblasts, regardless of the normal mRNA levels, suggesting that the mutated residues might be important for TIMM50 protein stability. Severe morphological defects and ultrastructural abnormalities with aberrant mitochondrial cristae organization in muscle and fibroblasts were found. The levels of fully assembled OXPHOS complexes and supercomplexes were strongly reduced in fibroblasts from this patient. High‐resolution respirometry demonstrated a significant reduction of the maximum respiratory capacity. A TIMM50‐deficient HEK293T cell line that we generated using CRISPR/Cas9 mimicked the respiratory defect observed in the patient fibroblasts; notably, this defect was rescued by transfection with a plasmid encoding the TIMM50 wild‐type protein. In summary, we demonstrated that TIMM50 deficiency causes a severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology, such as the maintenance of proper mitochondrial morphology, OXPHOS assembly, and mitochondrial respiratory capacity.     

Poly(n‐alkyl methacrylate)s as Metallocene Catalyst Supports in Nonpolar Media

In this work, poly(alkylmethacrylates) based on poly(n‐alkyl methacrylate)s (PnAMAs), that is, poly(hexyl methacrylate) (PHMA), poly(lauryl methacrylate) (PLMA), and poly(stearyl methacrylate) (PSMA), with similar molar masses (M_n), are synthesized via reversible addition–fragmentation chain transfer technique using a high‐throughput approach. Analyses by dynamic light scattering (DLS) of PnAMAs in nonpolar solvents show the presence of nanoparticles distributions (unimers or single chains). Interactions of methylaluminoxane (MAO) and MAO/metallocene compounds with PnAMA nanoparticles, lead to self‐assembled micellar‐like structures useful as “nanoreactors” for coordination polymerizations of ethylene. The inverse micellar‐like structures of the three kinds of polymethacrylates, formed in the presence of MAO are confirmed by DLS experiments and by transmission electron microscopy using energy dispersive spectrometry analyzer, in dyed PnAMAs/MAO samples. The encapsulation of the metallocene catalyst into the PSMA/MAO nanoparticles reveals stable catalytic systems that have a clear effect on the morphology of the polyethylenes synthesized through this method.     

Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion

Chronic rejection accounts for most renal allograft losses after the first year posttransplantation. On March 24 and 25, 1997, a roundtable of five transplant surgeons, two nephrologists, and one pathologist assembled in Dallas, Texas, to review critical issues surrounding chronic renal allograft rejection. This article summarizes the presentations and relevant discussions of this meeting regarding the cause of chronic rejection, clinical diagnoses, risk factors, future prospects for intervention strategies, and general recommendations for the transplant community. Growing evidence indicates that chronic rejection is the aggregate sum of irreversible immunologic and nonimmunologic injuries to the renal graft over time. A history of acute rejection episodes and inadequate immunosuppression, likely attributable to inconsistent cyclosporine exposure or poor patient compliance, are among the most recognizable immunologic risk factors for chronic rejection. Donor organ quality, delayed graft function, and other donor and recipient variables leading to reduced nephron mass are nonimmunologic factors that contribute to the progressive deterioration of renal graft function. Clinical management of renal transplant recipients should incorporate both immunologic- and nonimmunologic-based intervention strategies aimed at minimizing risk factors to thwart the progression of chronic rejection and improve long-term allograft and patient survival.     

Correlation of quantitative ultrasound of bone with biochemical markers of bone resorption in women with osteoporotic fractures.

The purpose of this study was to examine the correlation of parameters of bone quality assessed by quantitative ultrasound (QUS) with biochemical indexes of bone resorption. QUS of the calcaneus and the hand phalanges, and biochemical parameters (urinary excretion of pyridinoline [Pyr] and deoxypyridinoline [D-Pyr]) were measured in a group of 30 well-characterized postmenopausal women with established osteoporosis and fragility fractures. All patients were treatment free. QUS data significantly correlated with both urinary Pyr and D-Pyr (p < 0.001 for speed of sound [SOS], broadband ultrasound attenuation [BUA], and stiffness at the heel; p < 0.001 for amplitude-dependent SOS at the proximal phalanges of the nondominant hand). No significant correlation was observed between spine and femoral bone mineral density and the urinary excretion of Pyr and D-Pyr. Results of this study suggest that QUS of bone evaluates characteristics of bone influenced by the bone resorption rate.     

Basic fibroblast growth factor enhances axonal sprouting after cortical injury in rats.

The trophic factors responsible for initiating and guiding the outgrowth of axons have proven to be elusive throughout most of this century. Entorhinal cortex injury, which denervates the hippocampal formation of rats, induces axonal sprouting by several surviving hippocampal afferents and results in a significant elevation of growth factors, one of which is basic fibroblast growth factor (bFGF). The possibility that bFGF may regulate lesion-induced hippocampal sprouting was examined by making i.v. bFGF infusions into rats with unilateral entorhinal lesions. Basic FGF treatment significantly increased sprouting by the cholinergic septodentate pathway. Thus, the increase in bFGF following central nervous system injury may signal its role in the regulation of injury-related axonal remodeling of a cholinergic pathway.