Impact of Nusinersen Treatment on Measures of Exercise Intolerance in Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, marked by insufficient production of SMN protein, leading to motor neuron dysfunction. Although ubiquitously produced throughout the body, motor neurons and muscle cells are selectively impacted by decreased SMN, which has been linked to impaired oxidative phosphorylation causing altered metabolic function and exercise intolerance. Nusinersen, administered directly to the central nervous (CNS), is an approved therapy that increases SMN protein in an effort to restore motor neuron function. PURPOSE: To evaluate the impact of treatment on markers of exercise tolerance in children and adults treated with nusinersen is not known. METHODS: Nusinersen treated ambulatory children and adults with SMA completed a maximal cardiopulmonary exercise (CPX) test on a cycle ergometer at two visits 6 months apart. Oxygen uptake (VO2) at peak exercise, oxygen uptake efficiency slope (OUES), and ventilatory equivalent for oxygen (VE/VO2) at peak exercise were determined. Paired sample t-tests were used to evaluate change between visits. RESULTS: Nine ambulatory children and adults with SMA (89% male) (mean age=32.4, range=13-57 years) were included. The average length of time participants had received treatment was 1.05 years (range= 0.59 – 1.30 years). VO2 significantly increased from 13.49 ml·kg-1· min-1 to 16.52 ml·kg-1· min-1 (P = 0.03), OUES increased from 1324 to 1495 ml·min-1 O2/L· min-1,and VE/VO2 increased from 44.9 to 49.0 after 6-months. No significant differences were found in OUES or VE/VO2 after six months of treatment.(P\u3c 0.05) CONCLUSION: These results show potential to mitigate exercise intolerance with nusinersen treatment in individuals with SMA. VO2 was significantly improved, but an attenuated OUES and exaggerated hyperventilation response, representative measures of efficiency, persists. As aerobic capacity reflects the integrative function of multiple body systems, the improvement observed may be attributed to tissues not directly targeted by Nusinersen. Exercise testing is a valuable method of assessing muscle oxygen kinetics and suggested mitochondrial dysfunction observed in SMA. Combining exercise with drug therapies may further enhance benefits seen by treatment alone and developing specific muscle-targeted therapies may be warranted

A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia

We report a genome-wide association scan in >6,000 Latin Americans for pigmentation of skin and eyes. We found eighteen signals of association at twelve genomic regions. These include one novel locus for skin pigmentation (in 10q26) and three novel loci for eye pigmentation (in 1q32, 20q13 and 22q12). We demonstrate the presence of multiple independent signals of association in the 11q14 and 15q13 regions (comprising the GRM5/TYR and HERC2/OCA2 genes, respectively) and several epistatic interactions among independently associated alleles. Strongest association with skin pigmentation at 19p13 was observed for an Y182H missense variant (common only in East Asians and Native Americans) in MFSD12, a gene recently associated with skin pigmentation in Africans. We show that the frequency of the derived allele at Y182H is significantly correlated with lower solar radiation intensity in East Asia and infer that MFSD12 was under selection in East Asians, probably after their split from Europeans

Signaling pathway networks mined from human pituitary adenoma proteomics data

Abstract Background We obtained a series of pituitary adenoma proteomic expression data, including protein-mapping data (111 proteins), comparative proteomic data (56 differentially expressed proteins), and nitroproteomic data (17 nitroproteins). There is a pressing need to clarify the significant signaling pathway networks that derive from those proteins in order to clarify and to better understand the molecular basis of pituitary adenoma pathogenesis and to discover biomarkers. Here, we describe the significant signaling pathway networks that were mined from human pituitary adenoma proteomic data with the Ingenuity pathway analysis system. Methods The Ingenuity pathway analysis system was used to analyze signal pathway networks and canonical pathways from protein-mapping data, comparative proteomic data, adenoma nitroproteomic data, and control nitroproteomic data. A Fisher's exact test was used to test the statistical significance with a significance level of 0.05. Statistical significant results were rationalized within the pituitary adenoma biological system with literature-based bioinformatics analyses. Results For the protein-mapping data, the top pathway networks were related to cancer, cell death, and lipid metabolism; the top canonical toxicity pathways included acute-phase response, oxidative-stress response, oxidative stress, and cell-cycle G2/M transition regulation. For the comparative proteomic data, top pathway networks were related to cancer, endocrine system development and function, and lipid metabolism; the top canonical toxicity pathways included mitochondrial dysfunction, oxidative phosphorylation, oxidative-stress response, and ERK/MAPK signaling. The nitroproteomic data from a pituitary adenoma were related to cancer, cell death, lipid metabolism, and reproductive system disease, and the top canonical toxicity pathways mainly related to p38 MAPK signaling and cell-cycle G2/M transition regulation. Nitroproteins from a pituitary control related to gene expression and cellular development, and no canonical toxicity pathways were identified. Conclusions This pathway network analysis demonstrated that mitochondrial dysfunction, oxidative stress, cell-cycle dysregulation, and the MAPK-signaling abnormality are significantly associated with a pituitary adenoma. These pathway-network data provide new insights into the molecular mechanisms of human pituitary adenoma pathogenesis, and new clues for an in-depth investigation of pituitary adenoma and biomarker discovery.</p

Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: Guidance for prescribing exercise

The purpose of this Position Stand is to provide guidance to professionals who counsel and prescribe individualized exercise to apparently healthy adults of all ages. These recommendations also may apply to adults with certain chronic diseases or disabilities, when appropriately evaluated and advised by a health professional. This document supersedes the 1998 American College of Sports Medicine (ACSM) Position Stand, The Recommended Quantity and Quality of Exercise for Developing and Maintaining Cardiorespiratory and Muscular Fitness, and Flexibility in Healthy Adults. The scientific evidence demonstrating the beneficial effects of exercise is indisputable, and the benefits of exercise far outweigh the risks in most adults. A program of regular exercise that includes cardiorespiratory, resistance, flexibility, and neuromotor exercise training beyond activities of daily living to improve and maintain physical fitness and health is essential for most adults. The ACSM recommends that most adults engage in moderate-intensity cardiorespiratory exercise training for ≥30 min•d-1 on ≥5 d•wk-1 for a total of ≥150 min•wk-1, vigorous-intensity cardiorespiratory exercise training for ≥20 min•d-1 on ≥3 d•wk-1 (≥75 min•wk-1), or a combination of moderate-and vigorous-intensity exercise to achieve a total energy expenditure of ≥500-1000 MET•min•wk-1. On 2-3 d•wk-1, adults should also perform resistance exercises for each of the major muscle groups, and neuromotor exercise involving balance, agility, and coordination. Crucial to maintaining joint range of movement, completing a series of flexibility exercises for each the major muscle-tendon groups (a total of 60 s per exercise) on ≥2 d•wk-1 is recommended. The exercise program should be modified according to an individual\u27s habitual physical activity, physical function, health status, exercise responses, and stated goals. Adults who are unable or unwilling to meet the exercise targets outlined here still can benefit from engaging in amounts of exercise less than recommended. In addition to exercising regularly, there are health benefits in concurrently reducing total time engaged in sedentary pursuits and also by interspersing frequent, short bouts of standing and physical activity between periods of sedentary activity, even in physically active adults. Behaviorally based exercise interventions, the use of behavior change strategies, supervision by an experienced fitness instructor, and exercise that is pleasant and enjoyable can improve adoption and adherence to prescribed exercise programs. Educating adults about and screening for signs and symptoms of CHD and gradual progression of exercise intensity and volume may reduce the risks of exercise. Consultations with a medical professional and diagnostic exercise testing for CHD are useful when clinically indicated but are not recommended for universal screening to enhance the safety of exercise. Copyright © 2011 by the American College of Sports Medicine

Low Bone Mass in Ambulatory Spinal Muscular Atrophy: A Proactive Approach for an Often-Overlooked Impairment

Background: Individuals with spinal muscular atrophy (SMA) are at risk for low bone mass (LBM). The objectives of this study were to compare bone mineral density (BMD) in ambulatory SMA and control participants, identify LBM, and evaluate the associations of function and physical activity (PA) with LBM. Methods: Thirty-five children and adults, nineteen SMA and sixteen healthy controls, participated. Dual-energy absorptiometry determined BMD, T-scores, and Z-scores. The six-minute walk test (6MWT) and Timed Up and Go (TUG) assessed function. The International Physical Activity Questionnaire Short Form (IPAQ-SF) evaluated PA. Results: Group comparisons and factors associated with BMD were analyzed. Area under the receiver operating characteristic (ROC) curve (AUC) assessed the ability to identify individuals with LBM. SMA participants had lower BMD (p p = 0.004). Conclusions: Ten SMA and one control had LBM. Z-score was associated with 6MWT (rs = 0.65; p s = −0.61; p s = 0.36, p p = 0.006) and TUG (AUC: 0.85; 95% CI: 0.71–0.98; p = 0.002) identified individuals with LBM. Function, assessed by the 6MWT and TUG, is associated with BMD and shows promise for use in identifying individuals with LBM

Longitudinal changes in physical capacity from adolescence to middle age in men and women

The aim was to investigate how physical capacity changes from adolescence through early adulthood to middle age with focus on early aging. The aim was also to study if physical capacity in middle age could be predicted by factors in adolescence or early adulthood. A cohort of men and women in Sweden (SPAF-1958, n = 425) have been followed for 36 years, at 16, 34, and 52 years of age. The study includes, among other variables, objective measures of physical capacity. At age 52, 50% of the original cohort participated in exercise testing. Physical capacity increased from 16 to 34 years. From 34 to 52 years, physical capacity decreased in both genders by 15-20% in all but one test. Physical capacity at 16 and 34 years of age were better predictors of physical capacity at age 52 than body dimensions, school grades and life style factors. In conclusion, present data confirm earlier cross-sectional studies regarding the decrease in aerobic capacity and muscular strength during the early ageing period in both genders. The study has also generated novel data that show a smaller decline in muscular endurance than previously reported. Finally, physical capacity is fairly stable from adolescence to middle age