VO2max and Velocity at VO2max Play a Role in Ultradistance Trail-Running Performance.

Previous research has shown that maximal oxygen uptake (VO2max) significantly influences performance in trail-running races up to 120 km but not beyond. Similarly, the influence of running economy on performance in ultratrail remains unclear. The aim of our study was, therefore, to determine the physiological predictors of performance in a 166-km trail-running race. Thirty-three experienced trail runners visited the laboratory 4 to 8 weeks before the race to undergo physiological testing including an incremental treadmill test and strength assessments. Correlations and regression analyses were used to determine the physiological variables related to performance. Average finishing time was 37:33 (5:52) hours. Performance correlated significantly with VO2max (r = -.724, P < .001), velocity at VO2max (r = -.813, P < .001), lactate turn point expressed as percentage of VO2max (r = -.510, P = .018), cost of running (r = -.560, P = .008), and body fat percentage (r = .527, P = .012) but was not related to isometric strength. Regression analysis showed that velocity at VO2max predicted 65% of the variability in performance (P < .001), while a model combining VO2max and cost of running combined predicted 62% of the variability (P = .008). This is the first study to show that VO2max and velocity at VO2max are significant predictors of performance in a 166-km trail-running race. This suggests that ultratrail runners should focus on the development of these 2 qualities to optimize their race performance

Hemolysis induced by an extreme mountain ultra-marathon is not associated with a decrease in total red blood cell volume

Prolonged running is known to induce hemolysis. It has been suggested that hemolysis may lead to a significant loss of red blood cells; however, its actual impact on the erythrocyte pool is unknown. Here, we test the hypothesis that prolonged running with high hemolytic potential decreases total red blood cell volume (RCV). Hemolysis (n = 22) and RCV (n = 19) were quantified in ultra-marathon runners before and after a 166-km long mountain ultra-endurance marathon (RUN) with 9500 m of altitude gain/loss. Assessment of total hemoglobin mass (Hb(mass) ) and RCV was performed using a carbon monoxide rebreathing technique. RUN induced a marked acute-phase response and promoted hemolysis, as shown by a decrease in serum haptoglobin (P < 0.05). Elevated serum erythropoietin concentration and reticulocyte count after RUN were indicative of erythropoietic stimulation. Following RUN, runners experienced hemodilution, mediated by a large plasma volume expansion and associated with a large increase in plasma aldosterone. However, neither Hb(mass) nor RCV were found to be altered after RUN. Our findings indicate that mechanical/physiological stress associated with RUN promotes hemolysis but this has no impact on total erythrocyte volume. We therefore suggest that exercise 'anemia' is entirely due to plasma volume expansion and not to a concomitant decrease in RCV

Molecular adaptations of neuromuscular disease-associated proteins in response to eccentric exercise in human skeletal muscle

The molecular events by which eccentric muscle contractions induce muscle damage and remodelling remain largely unknown. We assessed whether eccentric exercise modulates the expression of proteinases (calpains 1, 2 and 3, proteasome, cathepsin B+L), muscle structural proteins (α-sarcoglycan and desmin), and the expression of the heat shock proteins Hsp27 and αB-crystallin. Vastus lateralis muscle biopsies from twelve healthy male volunteers were obtained before, immediately after, and 1 and 14 days after a 30 min downhill treadmill running exercise. Eccentric exercise induced muscle damage as evidenced by the analysis of muscle pain and weakness, creatine kinase serum activity, myoglobinaemia and ultrastructural analysis of muscle biopsies. The calpain 3 mRNA level was decreased immediately after exercise whereas calpain 2 mRNA level was increased at day 1. Both mRNA levels returned to control values by day 14. By contrast, cathepsin B+L and proteasome enzyme activities were increased at day 14. The α-sarcoglycan protein level was decreased immediately after exercise and at day 1, whereas the desmin level peaked at day 14. αB-crystallin and Hsp27 protein levels were increased at days 1 and 14. Our results suggest that the differential expression of calpain 2 and 3 mRNA levels may be important in the process of exercise-induced muscle damage, whereas expression of α-sarcoglycan, desmin, αB-crystallin and Hsp27 may be essentially involved in the subsequent remodelling of myofibrillar structure. This remodelling response may limit the extent of muscle damage upon a subsequent mechanical stress

Reversible endogenous downregulation of myostatin pathway in wasting neuromuscular diseases explains challenges of anti-myostatin therapeutic approaches

International audienc

Myostatin expression levels in neuromuscular diseases participates in anti-myostatin clinical failure

International audienc

Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches

Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin. We also provide in vivo evidence in the congenital myotubular myopathy mouse model (knock-out for the myotubularin coding gene Mtm1) that a down-regulated myostatin pathway can be reactivated by correcting the underlying gene defect. Our data may explain the poor clinical efficacy of anti-myostatin approaches in several of the clinical studies and the apparent contradictory results in mice regarding the efficacy of anti-myostatin approaches and may inform patient selection and stratification for future trials

P338 Clinical, morphological, and proteomic features of patients suspected of X-linked myopathy with excessive autophagy (XMEA)

XMEA is a slowly progressive disease that affects male patients and is defined by proximal limb muscle weakness. It is caused by hemizygous mutations in the VMA21 gene encoding a protein which assembles lysosomes’ proton pumps. We have studied eight patients from six new unrelated French families clinically suspected of XMEA. The clinical charts were reviewed, and extensive histological, immunohistochemical and electron microscopy analysis of the muscle biopsies were performed. Sanger sequencing or next generation panel of VMA21 gene was done. Proteomic profiling was carried out on muscle protein extracts derived from three of these patients. The patients presented typical clinical and pathological features of XMEA with onset during childhood or adulthood, proximal limb weakness and mildly elevated CK. Four patients had cardiac alterations and three of them have restrictive respiratory insufficiency. Muscle biopsy of patients showed numerous cytoplasmic vacuoles, segmented fibers, internalized nuclei and significant variability in fiber size. Vacuoles stained positive for sarcolemmal proteins, LAMP2, LC3, p62 and complement C5b-9. Ultrastructural evaluation revealed basal lamina duplication, subsarcolemmal and cytoplasmic vacuoles and extensive autophagosome extrusion. Proteomic results indicated complement activation and impaired proteolysis in addition to mitochondrial and cytoskeletal vulnerability. Molecular investigation disclosed two pathogenic variants in VMA21 (c.164-7T>G, n=5; c.163+4A>G, n=1) and a novel variant in the 3′UTR (c*124A>G, n=1). No mutation was found for one of the patients.In conclusion, we reported a novel mutation and a new clinical aspect with the presence of cardiac abnormalities. Although all muscle biopsies mimic XMEA, we failed to identify VMA21 mutation in one patient suggesting the involvement of additional genes in this unique histopathology. Proteomic findings provide insights into the underlying pathophysiology