‘Weak by Structure’—Limb Muscle Fibre Cytoarchitecture Remodelling During Critical Illness and Effects of Chaperone Co-Inducer BGP-15 and Dissociative Glucocorticoid VBP-15

Critical illness myopathy (CIM) is linked to mechanical ventilation and complete mechanical muscle silencing in intensive care unit (ICU) patients. Limb muscles show atrophy and declined specific single fibre force through altered protein turnover and diminished myosin-to-actin ratios. A rat ICU model reproducing preferential myosin loss and specific force decline in limb muscle was used to assess myofibrillar remodelling. After 5 or 10 days of ICU intervention, single extensor digitorum longus (EDL) and soleus muscle fibres were imaged using label-free, Second Harmonic Generation (SHG) microscopy, followed by quantitative 3D morphometry. The degree and severity of deranged myofibrillar architecture was assessed through (i) 2D and 3D Cosine Angle Sums (CAS2D/CAS3D) and (ii), Vernier Densities (VD) parameters. A progressively declining myofibrillar order was seen by dropping CAS2D/3D and increasing VD values during ICU intervention, reflecting angular and axial register deviations. Effects of chaperone co-inducer BGP-15, dissociative glucocorticoid Vamorolone (VBP-15) or its parent compound Prednisolone on myofibrillar architecture were explored. Both BGP-15 and VBP-15 modulated the progression of myofibrillar disorder seen during ICU intervention alone: For soleus fibres, BGP-15 maintained structural integrity at day 5 but not at day 10, while even worsening myofibrillar order in the EDL. VBP-15 reversed atrophy at day 10 in soleus but not in EDL fibres. Our study is the first to quantify myofibrillar remodelling in limb muscle fibres during ICU intervention in 3D and provides exploratory assessment of BGP-15 and VBP-15 treatments on aberrant remodelling in CIM.