Acute hypoxia reduces plasma myostatin independent of hypoxic dose

Background: Muscle atrophy is seen ~ 25 % of patients with cardiopulmonary disorders, such as chronic obstructive pulmonary disorder and chronic heart failure. Multiple hypotheses exist for this loss, including inactivity, inflammation, malnutrition and hypoxia. Healthy individuals exposed to chronic hypobaric hypoxia also show wasting, suggesting hypoxia alone is sufficient to induce atrophy. Myostatin regulates muscle mass and may underlie hypoxic-induced atrophy. Our previous work suggests a decrease in plasma myostatin and increase in muscle myostatin following 10 hours of exposure to 12 % O2. Aims: To establish the effect of hypoxic dose on plasma myostatin concentration. Concentration of plasma myostatin following two doses of normobaric hypoxia (10.7 % and 12.3 % O2) in a randomised, single-blinded crossover design (n = 8 lowlanders, n = 1 Sherpa), with plasma collected pre (0 hours), post (2 hours) and 2 hours following (4 hours) exposure. Results: An effect of time was noted, plasma myostatin decreased at 4 hours but not 2 hours relative to 0 hours (p = 0.01; 0 hours = 3.26 [0.408] ng.mL-1, 2 hours = 3.33, [0.426] ng.mL-1, 4 hours = 2.92, [0.342] ng.mL-1). No difference in plasma myostatin response was seen between hypoxic conditions (10.7 % vs. 12.3 % O2). Myostatin reduction in the Sherpa case study was similar to the lowlander cohort. Conclusions: Decreased myostatin peptide expression suggests hypoxia in isolation is sufficient to challenge muscle homeostasis, independent of confounding factors seen in chronic cardiopulmonary disorders, in a manner consistent with our previous work. Decreased myostatin peptide may represent flux towards peripheral muscle, or a reduction to protect muscle mass. Chronic adaption to hypoxia does not appear to protect against this response, however larger cohorts are needed to confirm this. Future work will examine tissue changes in parallel with systemic effects.

Detailed phenotypic and genotypic characterization of bietti crystalline dystrophy

OBJECTIVE: To provide a detailed phenotype/genotype characterization of Bietti crystalline dystrophy (BCD). DESIGN: Observational case series. PARTICIPANTS: Twenty patients from 17 families recruited from a multiethnic British population. METHODS: Patients underwent color fundus photography, near-infrared (NIR) imaging, fundus autofluorescence (FAF) imaging, spectral domain optical coherence tomography (SD-OCT), and electroretinogram (ERG) assessment. The gene CYP4V2 was sequenced. MAIN OUTCOME MEASURES: Clinical, imaging, electrophysiologic, and molecular genetics findings. RESULTS: Patients ranged in age from 19 to 72 years (median, 40 years), with a visual acuity of 6/5 to perception of light (median, 6/12). There was wide intrafamilial and interfamilial variability in clinical severity. The FAF imaging showed well-defined areas of retinal pigment epithelium (RPE) loss that corresponded on SD-OCT to well-demarcated areas of outer retinal atrophy. Retinal crystals were not evident on FAF imaging and were best visualized with NIR imaging. Spectral domain OCT showed them to be principally located on or in the RPE/Bruch's membrane complex. Disappearance of the crystals, revealed by serial recording, was associated with severe disruption and thinning of the RPE/Bruch's membrane complex. Cases with extensive RPE degeneration (N = 5) had ERGs consistent with generalized rod and cone dysfunction, but those with more focal RPE atrophy showed amplitude reduction without delay (N = 3), consistent with restricted loss of function, or that was normal (N = 2). Likely disease-causing variants were identified in 34 chromosomes from 17 families. Seven were novel, including p.Met66Arg, found in all 11 patients from 8 families of South Asian descent. This mutation appears to be associated with earlier onset (median age, 30 years) compared with other substitutions (median age, 41 years). Deletions of exon 7 were associated with more severe disease. CONCLUSIONS: The phenotype is highly variable. Several novel variants are reported, including a highly prevalent substitution in patients of South Asian descent that is associated with earlier-onset disease. Autofluorescence showed sharply demarcated areas of RPE loss that coincided with abrupt edges of outer retinal atrophy on SD-OCT; crystals were generally situated on or in the RPE/Bruch's complex but could disappear over time with associated RPE disruption. These results support a role for the RPE in disease pathogenesis.

The role of acute ambient hypoxia in the regulation of myostatin

When exposed to chronic hypoxia by pathophysiological or environmental causes humans show muscle atrophy, challenging homeostasis and increasing mortality rate. Chronic hypoxia also presents with elevated myostatin peptide, a negative regulator of muscle size. This work induced acute hypoxia in healthy individuals; hypothesizing hypoxia would increase myostatin expression in both muscle and plasma in a concentration- and time-dependent manner. Hypoxia (1 % O2) reduced C2C12 myoblast migration and myotube size in vitro. Myotube atrophy was time-dependent, longer exposures showed greater atrophy. Intracellular myostatin peptide was decreased at every time point measured. Myostatin and downstream signalling pathways in muscle showed a high degree of percentage similarity between mouse and human, when amino acid sequences were directly compared. Healthy males (N = 8) were exposed to 20.9 % O2 or 11.9 % O2 for 2 hours. Following hypoxic exposure myostatin peptide was reduced in muscle but not plasma, relative to control conditions. A second cohort (N = 8) was exposed to 12.5 % O2 for 10 hours. Plasma myostatin was decreased following hypoxia, muscle myostatin trended towards increasing. A third cohort (N = 9; n = 8 lowlander, n = 1 Sherpa) was exposed to 10.7 % or 12.3 % O2 for 2 hours. Plasma myostatin was reduced at both concentrations with no difference between concentrations noted. In response to chronic hypoxia, individuals lose muscle mass. Counter to the hypothesis of an increase in myostatin in both muscle and plasma, here a consistent decrease in plasma myostatin following acute hypoxia is seen. Muscle myostatin shows a variable response, with decreasing intracellular expression seen following a 2 hour hypoxic exposure, and trends towards an increase following 10 hours of hypoxia. Decreases in plasma and muscle myostatin may represent myostatin’s movement towards peripheral compartments in these acute timeframes. Hypoxia alone is capable of altering myostatin in healthy individuals; the effects of hypoxia on myostatin appear to differ between the acute timeframes examined here and chronic exposures in environmental or disease models.