Effect of Changing Heart Rate on the Ocular Pulse and Dynamic Biomechanical Behavior of the Optic Nerve Head.

Purpose: To study the effect of changing heart rate on the ocular pulse and the dynamic biomechanical behavior of the optic nerve head (ONH) using a comprehensive mathematical model. Methods: In a finite element model of a healthy eye, a biphasic choroid consisted of a solid phase with connective tissues and a fluid phase with blood, and the lamina cribrosa (LC) was viscoelastic as characterized by a stress-relaxation test. We applied arterial pressures at 18 ocular entry sites (posterior ciliary arteries), and venous pressures at four exit sites (vortex veins). In the model, the heart rate was varied from 60 to 120 bpm (increment: 20 bpm). We assessed the ocular pulse amplitude (OPA), pulse volume, ONH deformations, and the dynamic modulus of the LC at different heart rates. Results: With an increasing heart rate, the OPA decreased by 0.04 mm Hg for every 10 bpm increase in heart rate. The ocular pulse volume decreased linearly by 0.13 µL for every 10 bpm increase in heart rate. The storage modulus and the loss modulus of the LC increased by 0.014 and 0.04 MPa, respectively, for every 10 bpm increase in heart rate. Conclusions: In our model, the OPA, pulse volume, and ONH deformations decreased with an increasing heart rate, whereas the LC became stiffer. The effects of blood pressure/heart rate changes on ONH stiffening may be of interest for glaucoma pathology.

Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia.

Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia.