Acute and severe trabecular bone loss in a rat model of critical illness myopathy

Abstract

Prolonged mechanical ventilation for critically ill patients with respiratory distress can result in severe muscle wasting with preferential loss of myosin. Systemic inflammation triggered by lung mechanical injury likely contributes to this myopathy, although the exact mechanisms are unknown. In this study, we hypothesized that muscle wasting following mechanical ventilation is accompanied by bone loss. The objective was to determine the rate, nature, and extent of bone loss in the femora of rats ventilated up to 10 days and to relate the bone changes to muscle deterioration. We have developed a rat model of ventilatorinduced muscle wasting and established its feasibility and clinical validity. This model involves pharmacologic paralysis, parenteral nutrition, and continuous mechanical ventilation. We assessed the hindlimb muscle and bone of rats ventilated for 0, 2, 5, 8, and 10 days. Routine histology, microCT, and biomechanical evaluations were performed. Hindlimb muscles developed changes consistent with myopathy, whereas the femurs demonstrated a progressive decline in trabecular bone volume, mineral density, and microarchitecture beginning Day 8 of mechanical ventilation. Biomechanical testing showed a reduction in flexural strength and stiffness on Day 10. The bone changes correlated with the loss of muscle mass and myosin. These results demonstrate that mechanical ventilation leads to progressive trabecular bone loss parallel to muscle deterioration. The results of our study suggest that mechanically ventilated patients may be at risk of compromised bone integrity and muscle weakness, predisposing to post-ventilator falls and fractures, thereby warranting interventions to prevent progressive bone and muscle decline.

Why Does Inflammation Result in Resorptive Bone Loss? What the Study of Burns Teaches Us

“…TRPV4 has also been implicated in macrophage activation leading to lung injury following mechanical ventilation. These issues have also been reported in a rat model of immobilization and mechanical ventilation [20] in which it was shown that the pharmacologic immobilization of rats was accompanied by marked trabecular bone loss, thus liberating calcium into the circulation and possibly contributing to the inflammation described by Michalick and Kuebler [19].…”

“…This has been demonstrated in cardiomyocytes [45]. A similar mechanism has been described for the initiation of inflammation in mechanical ventilation [20], and a related mechanism has been implicated following cardiac ischemia, also involving a Ca 2+ /calmodulin regulated kinase [46]. It is unclear how much circulating Ca is necessary to trigger these latter effects, or if there is a threshold for circulating Ca to contribute to these effects.…”

Factores asociados al desarrollo de polineuropatía, miopatía y polineuromiopatía en pacientes adultos críticos

“…Se postula que esta asociación podría intensificarse a medida que aumentan los días de permanencia en la UCI debido a la severidad de la enfermedad y la activación de cascadas inflamatorias, lo que podría predisponer a una mayor probabilidad de lesión de las fibras musculares o denervación de las mismas 20 . De este modo, Gugala et al 21 destacan que los mecanismos patofisiológicos de la miopatía evolucionan con el tiempo durante la estancia en UCI, involucrando disfunción en la excitabilidad de las membranas musculares, desbalance en la homeostasis del calcio, fallo bioenergético y problemas en la funcionalidad de las proteínas motoras.…”

Transforming Growth Factor-Beta in Skeletal Muscle Wasting

“…We do not have evidence implicating bone-released TGF-β's involvement in immobilization to date. However, a recent study by Gugala et al [31] provides suggestive information. Studies of a rat model of critical illness myopathy developed by Llano Diez et al [32] have shown that by pharmacologically immobilizing rats and mechanically ventilating them for 10 days, a model that reproduces the effects of immobilization and the mechanical ventilation of patients in intensive care for COVID-19 respiratory disease, the loss of appendicular skeletal muscle mass and, in particular, myosin, occurs in tight correlation with the loss of trabecular bone, as determined by serial micro computed tomography of the femurs of rats studied from 0-10 days post-immobilization.…”