Impact of prolonged sepsis on neural and muscular components of muscle contractions in a mouse model

Abstract

Background Prolonged critically ill patients frequently develop debilitating muscle weakness that can affect both peripheral nerves and skeletal muscle. In‐depth knowledge on the temporal contribution of neural and muscular components to muscle weakness is currently incomplete. Methods We used a fluid‐resuscitated, antibiotic‐treated, parenterally fed murine model of prolonged (5 days) sepsis‐induced muscle weakness (caecal ligation and puncture; n = 148). Electromyography (EMG) measurements were performed in two nerve–muscle complexes, combined with histological analysis of neuromuscular junction denervation, axonal degeneration, and demyelination. In situ muscle force measurements distinguished neural from muscular contribution to reduced muscle force generation. In myofibres, imaging and biomechanics were combined to evaluate myofibrillar contractile calcium sensitivity, sarcomere organization, and fibre structural properties. Myosin and actin protein content and titin gene expression were measured on the whole muscle. Results Five days of sepsis resulted in increased EMG latency (P = 0.006) and decreased EMG amplitude (P < 0.0001) in the dorsal caudal tail nerve–tail complex, whereas only EMG amplitude was affected in the sciatic nerve–gastrocnemius muscle complex (P < 0.0001). Myelin sheath abnormalities (P = 0.2), axonal degeneration (number of axons; P = 0.4), and neuromuscular junction denervation (P = 0.09) were largely absent in response to sepsis, but signs of axonal swelling [higher axon area (P < 0.0001) and g‐ratio (P = 0.03)] were observed. A reduction in maximal muscle force was present after indirect nerve stimulation (P = 0.007) and after direct muscle stimulation (P = 0.03). The degree of force reduction was similar with both stimulations (P = 0.2), identifying skeletal muscle, but not peripheral nerves, as the main contributor to muscle weakness. Myofibrillar calcium sensitivity of the contractile apparatus was unaffected by sepsis (P ≥ 0.6), whereas septic myofibres displayed disorganized sarcomeres (P < 0.0001) and altered myofibre axial elasticity (P < 0.0001). Septic myofibres suffered from increased rupturing in a passive stretching protocol (25% more than control myofibres; P = 0.04), which was associated with impaired myofibre active force generation (P = 0.04), linking altered myofibre integrity to function. Sepsis also caused a reduction in muscle titin gene expression (P = 0.04) and myosin and actin protein content (P = 0.05), but not the myosin‐to‐actin ratio (P = 0.7). Conclusions Prolonged sepsis‐induced muscle weakness may predominantly be related to a disruption in myofibrillar cytoarchitectural structure, rather than to neural abnormalities.

Chronic critical illness and post-intensive care syndrome: from pathophysiology to clinical challenges

“…Although CIP persists in nearly half of surviving ICU patients [ 16 , 17 ], both animal and human studies suggest that the neural component is little involved in sustained ICUAW. Conversely, alteration of the muscle component would be the main mechanism [ 10 , 18 ]. Sustained weakness following CIM is characterized by strength loss due to impaired contractility and muscle wasting .…”

SEMPAI: a Self-Enhancing Multi-Photon Artificial Intelligence for prior-informed assessment of muscle function and pathology

“…Table 1), ML and especially DL are severely limited due to overfitting. Based on the identified associations of the same priors with the investigated labels in previous studies 5, 13, 35, 36 , we hypothesize that our muscle-specific learning tasks are related and the mean predictive performance over all tasks may assist SEMPAI to select a regularized model. Therefore, a total meta-loss is introduced, which is a weighted sum of all meta-losses for each task and provides an estimate of the model performance over all tasks.…”

“…In brief, these features include the cosine angle sum (CAS) taken from selected 2D planes (2D-CAS) and in 3D (3D-CAS), the vernier density (VD), the 3D sarcomere length (3D-SL), and the crosssectional area (CSA) of single fibers. Since these features have already been shown to be descriptive for a variety of rather specific remodeling patterns in muscle research, related to aging, chronic degenerative or inflammatory myopathies 5, 13, 35, 36 , we use them as prior information, and term them accordingly as priors . A more elaborate explanation of the extraction of priors is given in the Methods.…”

“…Duchenne muscular dystrophy (DMD), for instance, is caused by an overall loss of structural integrity in individual fibers, eventually leading to failure of respiratory and heart muscle that can be life-limiting 4 . Besides chronic degenerative diseases like DMD, also acute myopathies can result in disruptions of the myofibrillar structural alignment, as it has been shown in ongoing sepsis 5 .…”

Vitamin D Promotes Remyelination by Suppressing c-Myc and Inducing Oligodendrocyte Precursor Cell Differentiation after Traumatic Spinal Cord Injury

“…Axons with a diameter ranging from 800 to 1000 nm were opted for myelin measurement. G-ratio (the ratio between the inner and the outer diameter) was further analyzed using ImageJ software 24 . Images were demonstrated in 5,200X and 28,500X magnification except for the epicenter in transection group due to extensive demyelination, where lower power at 1,650X and 5,200X were used instead.…”