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.

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.…”