Odile Mathieu-Costello

Capillary tortuosity and degree of contraction or extension of skeletal muscles.

The effect of muscle contraction, and extension, on capillary anisotropy was investigated in rat m. soleus fixed by vascular perfusion at sarcomere lengths ranging from 1.62 micron (tetanizing stimulation of sciatic nerve) to 2.85 micron (ankle joint maximally flexed. Capillary length density and tortuosity were estimated by morphometry using two sets of sections (0 and 90 degrees to the fiber axis). Capillary orientation distribution was evaluated from a series of sections taken at 0 to 90 degrees (by steps of 5-10 degrees) to the fiber axis in six preparations (sarcomere length range, 1.62-2.85 micron; capillary length density, 900-2000 mm-2). The Fisher axial distribution provided a good fit for modeling capillary orientation distribution in each case. For a comparable capillary length density per volume of muscle fiber (approximately equal to 2000 mm-2), the degree of orientation of capillary segments parallel to the fiber axis was two and four times larger in extended m. soleus than in the muscles fixed at 1.98- and 1.62-micron sarcomere lengths, respectively. In preparations fixed at 2.85, 1.98, and 1.62 micron, capillary length density per volume of muscle fiber was, respectively, 14, 44, and 65% larger than revealed by capillary counts per sectional area of muscle fiber on transverse section only, an often used parameter to compare capillarity in different muscles.

Vulnerability of Pulmonary Capillaries in Heart Disease

The pulmonary blood-gas barrier presents a dilemma. It must be extremely thin for efficient gas exchange. However, it also needs to be immensely strong because the stresses in the pulmonary capillary wall become extremely high when the capillary pressure rises. Stress failure of the capillaries occurs in several pathological conditions. It causes high-permeability edema as in neurogenic pulmonary edema or high-altitude pulmonary edema; alveolar hemorrhage, which occurs in all galloping racehorses; or a combination of the two as in severe congestive heart failure. The vulnerability of the capillary wall to increased mechanical stress has not previously been sufficiently appreciated.

Limited maximal exercise capacity in patients with chronic heart failure: partitioning the contributors.

OBJECTIVES This study aimed to assess the factors limiting maximal exercise capacity in patients with chronic heart failure (CHF). BACKGROUND Maximal exercise capacity, an important index of health in CHF, might be limited by central and/or peripheral factors; however, their contributions remain poorly understood. METHODS We studied oxygen (O2) transport and metabolism at maximal cycle (centrally taxing) and knee-extensor (KE) (peripherally taxing) exercise in 12 patients with CHF and 8 healthy control subjects in normoxia and hyperoxia (100% O2). RESULTS Peak oxygen uptake (VO2) while cycling was 33% lower in CHF patients than in control subjects. By experimental design, peak cardiac output was reduced during KE exercise when compared with cycling (approximately 35%); although muscle mass specific peak leg VO2 was increased equally in both groups (approximately 70%), VO2 in the CHF patients was still 28% lower. Hyperoxia increased O2 carriage in all cases but only facilitated a 7% increase in peak leg VO2 in the CHF patients during cycling, the most likely scenario to benefit from increased O2 delivery. Several relationships, peak leg VO2 (KE + cycle) to capillary-fiber-ratio and capillaries around a fiber to mitochondrial volume, were similar in both groups (r = 0.6-0.7). CONCLUSIONS Multiple independent observations, including a significant skeletal muscle metabolic reserve, suggest skeletal muscle per se contributes minimally to limiting maximal cycle exercise in CHF or healthy control subjects. However, the consistent attenuation of the convective and diffusive components of O2 transport (25% to 30%) in patients with CHF during both cycle and even KE exercise compared with control subjects reveals an underlying peripheral O2 transport limitation from blood to skeletal muscle in this pathology.

Pulmonary microvascular permeability : responses to high vascular pressure after induction of pacing-induced heart failure in dogs

The pressure threshold for injury of pulmonary capillaries is approximately 50 to 55 cm H2O in the canine lung, as measured by changes in the filtration coefficient (Kf,c). Since the pulmonary endothelial basement membrane has been observed to thicken in patients with heart failure and pulmonary venous hypertension, we hypothesized that both baseline permeability and the threshold for high-vascular-pressure injury would be altered as a result. Dogs (n = 12) were chronically paced at 245 beats per minute for approximately 4 weeks, then were paced at 225 beats per minute for an additional 3 weeks. Lung lobes from anesthetized paced dogs and additional control dogs (n = 14) were then isolated, ventilated, and perfused with blood. Although vascular resistance was increased nearly threefold and vascular compliance reduced by 50% in the paced group, Kf,c referenced to 1 g blood-free dry weight was no different from control. Despite this lack of difference at normal pulmonary vascular pressures, several significant results were obtained. First, in the paced group there was a significant increase in the threshold for high-vascular-pressure injury: Kf,c measured at pulmonary vascular pressures commonly seen in heart failure (20 to 50 cm H2O) were significantly less in this group compared with control. Model predictions showed that in vivo, this difference in Kf,c would result in a 50% reduction in the amount of water and protein cleared across the pulmonary capillary endothelial barrier in the paced group.(ABSTRACT TRUNCATED AT 250 WORDS)

Capillary-to-fiber geometry and mitochondrial density in hummingbird flight muscle.

We investigated structural characteristics for high O2 flux in hummingbird flight muscle, i.e. the most O2 demanding skeletal muscle per unit tissue mass among vertebrates. Pectoralis and supracoracoideus muscles of 3-4 g hummingbirds (Selaphorus rufus) were perfusion fixed in situ, processed for electron microscopy and analyzed by morphometry. Small fiber size (group mean +/- SE, 201 +/- 14 microns 2 at 2.1 microns sarcomere length), large capillary length per fiber volume (8947 +/- 869 mm-2) and high mitochondrial volume density per volume of muscle fiber (34.5 +/- 0.9%) were characteristic features of the muscles. Considering capillary supply and mitochondrial volume on an individual fiber basis showed that the size of the capillary-to-fiber interface (i.e. capillary surface per fiber surface) was also high in the muscles. Comparison with mammalian hindlimb pointed to a major role of the size of the capillary-to-fiber interface in providing a great potential for O2 flux rate from capillary to muscle fiber mitochondria in hummingbird flight muscle.

Relationship Between Fiber Capillarization and Mitochondrial Volume Density in Control and Trained Rat Soleus and Plantaris Muscles

Objective: The majority of investigations have demonstrated a strong relationship between muscle capillarity and oxidative capacity. There is, however, evidence that die capacities for O2 supply and utilization can be dissociated. Also, metabolite removal rather man O2 supply may represent the predominant design constraint placed on the capillary bed in some muscles (i.e., fast‐twitch glycolytic). Recent evidence suggests mat the principal barrier to O2 diffusion in skeletal muscle resides between the red blood cell and the immediately subjacent sarcolemmal space. Consequendy, if the primary design constraint placed on the capillary bed is to facilitate O2 exchange, we hypothesized that capillary surface per fiber surface should be correlated with die mitochondrial volume subserved. Thus, the purpose of this study was to investigate whether one single relationship would be found between the capillary‐to‐fiber surface ratio and fiber mitochondrial volume in slow‐ (soleus) and fast‐twitch (plantaris) muscle and whether this relationship would be preserved after training.

Electron paramagnetic spectroscopic evidence of exercise-induced free radical accumulation in human skeletal muscle

The present study determined if acute exercise increased free radical formation in human skeletal muscle. Vastus lateralis biopsies were obtained in a randomized balanced order from six males at rest and following single-leg knee extensor exercise performed for 2 min at 50% of maximal work rate (WRMAX) and 3 min at 100% WRMAX. EPR spectroscopy revealed an exercise-induced increase in mitochondrial ubisemiquinone [0.167 ± 0.055 vs. rest: 0.106 ± 0.047 arbitrary units (AU)/g total protein (TP), P < 0.05] and α-phenyl-tert-butylnitrone-adducts (112 ± 41 vs. rest: 29 ± 9 AU/mg tissue mass, P < 0.05). Intramuscular lipid hydroperoxides also increased (0.320 ± 0.263 vs. rest: 0.148 ± 0.071 nmol/mg TP, P < 0.05) despite an uptake of α-tocopherol, α-carotene and β-carotene. There were no relationships between mitochondrial volume density and any biomarkers of oxidative stress. These findings provide the first direct evidence for intramuscular free radical accumulation and lipid peroxidation following acute exercise in humans.

Stress failure of pulmonary capillaries as a limiting factor for maximal exercise

The pulmonary blood-gas barrier has a basic physiological dilemma. On the one hand it needs to be extremely thin for efficient gas exchange. On the other hand it also needs to be immensely strong because the stresses on the pulmonary capillary wall become extremely high when the capillary pressure rises on exercise. Maximal hydrostatic pressures in human pulmonary capillaries during exercise are not accurately known but must exceed 30 mmHg. In some animals, for example thoroughbred horses, the capillary pressure rises to about 100 mmHg. These pressures cause stresses in the capillary wall of 5–10 × 104 N·M−2 (50–100 kPa) which approach the breaking strength of collagen. The strength of the capillary wall on the thin side of the blood-gas barrier can be attributed to the type IV collagen of the extracellular matrix. Raising the capillary pressure to similar levels in experimental preparations causes ultrastructural changes in the wall including disruption of the capillary endothelium, alveolar epithelium, and basement membrane in the interstitium. Essentially all thoroughbred racehorses bleed into their lungs during exercise because they break their capillaries, and some elite human athletes apparently do the same. Avoiding stress failure of pulmonary capillaries poses a challenging problem for some species. Stress failure is a hitherto overlooked factor limiting maximal exercise.

Comparative aspects of the strength of pulmonary capillaries in rabbit, dog, and horse.

In previous studies of rabbit and dog lung, we demonstrated stress failure of pulmonary capillaries at high transmural pressures (Ptm). The Ptm necessary to elicit stress failure was 40 cmH2O higher in dog than rabbit, and the total blood-gas barrier (BGB) thickness was greater in dog than rabbit. This suggests that stress failure may be related to BGB thickness, and is consistent with the Laplace relationship which states that wall stress is proportional to capillary radius but inversely proportional to wall thickness. In the present studies, we compared BGB thickness and an index of capillary radius in lungs from 3 rabbits, 3 dogs, and 2 horses perfusion fixed at a Ptm of approximately 30 cmH2O. Thicknesses of the BGB were measured at right angles to the barrier at random points on the capillary wall determined by test line intersections. Capillary radius was determined from the mean of major and minor axes measured on electron micrographs. Capillary pressure for failure in the horse was taken to be the mean of pulmonary arterial and left atrial pressures observed in galloping thoroughbreds known to develop exercise-induced pulmonary hemorrhage, although the actual pressure required for failure may be less than this. Average capillary radii were 3.6, 3.4, and 3.2 microns for rabbits, dogs, and horses, respectively. We found that the BGB was thinnest in the rabbit, intermediate in the dog, and thickest in the horse. Calculated capillary wall stress values for the median total BGB thickness at a nominal Ptm of 30 cmH2O were 2.5 x 10(4), 1.7 x 10(4), and 1.5 x 10(4) N.m-2 for rabbits, dogs, and horses, respectively. This species ranking fits with the pressures required to cause stress failure which are approximately 50, 90, and 130 cmH2O in rabbit, dog, and horse, respectively. We conclude that the differences in capillary radius of curvature and BGB thickness account for some of the observed differences in Ptm necessary to cause stress failure. However, other factors may also be important in determining the strength of the BGB.

Increased fiber capillarization in flight muscle of finch at altitude.

We examined fiber capillarization and ultrastructure in the highly aerobic flight muscle of six gray crowned rosy finches (Leucosticte arctoa; mass 22.9 +/- 0.5 (SE) g) living at altitude (A; White Mountains of Eastern California; 4000 m) compared to eight sea-level (SL) house finches (Carpodacus mexicanus, mass, 19.8 +/- 0.6 g) of the same subfamily, Carduelinae. Capillary length per fiber volume (A, 10,400 +/- 409 mm(-2); SL, 7513 +/- 423; P < 0.001) and capillary-to-fiber ratio (A, 2.32 +/- 0.07; SL, 1.85 +/- 0.06; P < 0.001) were significantly greater in A, with no difference in fiber cross-sectional area compared to SL. Capillary geometry was significantly different in A, yielding a greater contribution of tortuosity and branching to capillary length than in SL. Capillary-to-fiber surface ratio and fiber mitochondrial volume were both greater in A, but their ratio was similar to SL, indicating a proportional increase in the size of the capillary to fiber interface and fiber mitochondrial volume in A to sustain high levels of aerobic capacity while living at altitude.