Dicer-mediated miRNA processing is not involved in controlling muscle mass during muscle atrophy

Muscle atrophy occurs in a variety of physiological and pathological conditions. Specific molecular networks that govern protein synthesis and degradation play important roles in controlling muscle mass under diverse catabolic states. MicroRNAs (miRNAs) were previously found to be regulators of protein synthesis and degradation, and their expressions in skeletal muscle were altered in muscle wasting conditions. However, functional roles of miRNAs in muscle atrophy are poorly understood. In this study, we generated tamoxifen-inducible Dicer knockout (iDicer KO) mice and subjected them to 2 weeks of single hindlimb denervation. The expression of Dicer mRNA was significantly reduced in muscle of the iDicer KO mice compared to that of WT mice. The loss of Dicer moderately reduced levels of muscle-enriched miRNAs, miR-1, miR-133a and miR-206 in both innervated and denervated muscles of the iDicer KO mice. We also found that the extent of denervation-induced muscle atrophy as well as changes of signaling molecules related to protein synthesis/degradation pathways in the iDicer KO mice were comparable to these in WT mice. Taken together, Dicer knockout in adult skeletal muscle did not affect denervation-induced muscle atrophy.

Matrix Metalloproteinase-9 is Involved in the Fibrotic Process in Denervated Muscles after Sciatic Nerve Trauma and Recovery

Fibrosis of the injured muscles is a problem of recovery from trauma and denervation. The aim of the work was to investigate the interconnection of matrix metalloproteinase-9 (ММР-9) activity in denervated muscles with fibrosis and to estimate its role in nerve restoration by the epineurial suture, fibrin-based glue, and polyethylene glycol hydrogel. The activity of matrix metalloproteinases was estimated by gelatin zymography. Collagen density in muscles was determined histochemically. An increased level of the active MMP-9 is associated with the fibrous changes in the denervated skeletal muscles and after an epineurial suture. The use of fibrin glue and polyethylene glycol hydrogel resulted in a lower level of collagen and ММР-9 activity, which may be a therapeutic target in the treatment of neuromuscular lesions, and has value in fibrosis analysis following microsurgical intervention for peripheral nerve reconstruction.

Cubital tunnel syndrome

Cubital tunnel syndrome (CuTS) is the second most common compression neuropathy of the upper limb, presenting with disturbance of ulnar nerve sensory and motor function. The ulnar nerve may be dynamically compressed during movement, statically compressed due to reduction in tunnel volume or compliance, and tension forces may cause ischaemia or render the nerve susceptible to subluxation, further causing local swelling, compression inflammation and fibrosis. Superiority of one surgical technique for the management of CuTS has not been demonstrated. Different techniques are selected for different clinical situations with simple decompression being the most common procedure due to its efficacy and low complication rate. Adjunctive distal nerve transfer for denervated muscles using an expendable motor nerve to restore the axon population in the distal nerve is in its infancy but may provide a solution for severe intrinsic weakness or paralysis. Cite this article: EFORT Open Rev 2021;6:743-750. DOI: 10.1302/2058-5241.6.200129

Satellite Cells and Neuromuscular Spindles in Long Term Denervated Skeletal Muscles

Satellite cells (SC) are quiescent cell located between the sarcolemma and basal lamina of the skeletal muscle fibers. The SC can get activated contributing to regeneration and/or growth of muscle. The neuromuscular spindles are mechanoreceptors located within the skeletal muscle and are considered as contractile regulatory unit. It is composed of intrafusal muscle fibers (IF), surrounded by a sheath and is parallel to extrafusal fibers. Denervation cause changes in skeletal muscles both in the SC and neuromuscular spindles. This study analyzed quantitatively the IF and SC in Wistar rats denervated for long period. The animals were divided into normal and denervated groups. The soleus and extensor longus digitorum longus were denervated experimentally during periods of 0, 12, 16, 19, 30 and 38 weeks. The percentage of SC immediately after denervation increases when compared to normal group and later decreases in both the groups. During the process of denervation, there was an increase in IF when compared with normal group. The percentage of SC reduces significantly between the periods of denervation in both the groups. The smaller percentage of SC corresponds to higher number of IF. Besides that the number of SC decreases after denervation. As for IF, with the increase in time in normal group, the number of fibers was unaltered. However, in the experimental group, with increase in the time of denervation, the percentage of SC decreases while there is increase in the number of IF significantly. In denervated muscles for long period, there is decrease in the percentage of SC and increase in IF. Our results suggest that the period between 16th and 19th week post denervation is the best time for reinnervation of denervated muscle.

Quantitative assessment of intraneural vascular alterations in peripheral nerve trauma using high-resolution neurosonography: technical note

High-resolution neurosonography (HRNS) has become a major imaging modality in assessment of peripheral nerve trauma in the recent years. However, the vascular changes of traumatic lesions have not been quantitatively assessed in HRNS. Here, we describe the vascular-ratio, a novel HRNS-based quantitative parameter for the assessment of intraneural vascular alterations in patients with nerve lesions. N = 9 patients suffering from peripheral nerve trauma were examined clinically, electrophysiologically and with HRNS (SonoSite Exporte, Fuji). Image analyses using Fiji included determination of the established fascicular ratio (FR), the cross-section ratio (CSR), and as an extension, the calculation of a vascular ratio (VR) of the healthy versus damaged nerve and a muscle perfusion ratio (MPR) in comparison to a healthy control group. The mean VR in the healthy part of the affected nerve (14.14%) differed significantly (p < 0.0001) from the damaged part (VR of 43.26%). This coincides with significant differences in the FR and CSR calculated for the damaged part versus the healthy part and the controls. In comparison, there was no difference between VRs determined for the healthy part of the affected nerve and the healthy controls (14.14% / 17.72%). However, the MPR of denervated muscles was significantly decreased compared to the non-affected contralateral controls. VR and MPR serve as additional tools in assessing peripheral nerve trauma. Image analysis and calculation are feasible. Combined with the more morphologic FR and CSR, the VR and MPR provide a more detailed insight into alterations accompanying nerve trauma.

Upper and lower motor neuron lesions in tetraplegia: implications for surgical nerve transfer to restore hand function

Nerve transfers (neurotizations) performed under optimal conditions can restore some voluntary control in muscles of the upper extremities in patients with tetraplegia. However, the type of motoneuron lesions in target muscles for nerve transfers influences the functional outcome. Using standardized maps of motor point topography, surface electrical stimulation reliably defines the kind and extent of motoneuron lesion in the selected muscles. In a muscle with an intact lower motor motoneuron, nerve transfers can often successfully reinnervate the chosen key muscle. Conversely, in a lower motoneuron lesion, the nerve transfer outcome is less predictable. However, direct muscle stimulation appears to ameliorate the morphological precondition, a finding that necessitates new preoperative approaches to optimize reinnervation in denervated/partially denervated muscles. Therefore, understanding the impact of electrical stimulation in diagnostics, prognostics, and treatments of upper limbs in tetraplegia is critical for neurotization procedures.

Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika Virus Infection

The 2015–2017 Zika Virus outbreak caused a high increase in patients with Guillain-Barré syndrome (GBS), a post infectious autoimmune disease of the peripheral nerves. The severity of GBS can range from mild impairment with fast recovery to complete paralysis including severe respiratory or autonomic failure. Recovery may take months and even years and may be incomplete despite disease modifying treatment with IVIG or plasma exchange. Therefore, optimal supportive care and effective rehabilitation remain crucial. Multidisciplinary rehabilitation is recommended but may be challenging in the acute phase because of limited patient participation due to profound muscle weakness and severe pain. Inactive denervated muscles will inevitably undergo rapid degeneration resulting in wasting, weakness, and contractures as major long-term complications in severely affected patients. In this chapter, the current evidence of rehabilitation on the short- and long-term motor function in GBS is reviewed, including newly obtained experiences with neuromuscular electrical stimulation (NMES). Rehabilitation remains an area lacking well designed and controlled clinical studies and thus a clear lack of evidence-based guidelines.

Human Permanent Denervated Muscles Recovery

We demonstrated the long-term clinical value of co-activating thigh muscles through hbFES strategy using high currents and large surface electrodes. This Vienna Strategy is able to reverse, at clinically relevant levels, the adverse effects of Spinal Cord Injury (SCI), even in the worst-case scenario of complete lesion of lower motor neurons, as it may occur in complete conus and cauda equina syndrome. Continued regularly, hbFES for denervated, degenerating muscles helps to maintain healthier leg muscles and skin, reducing the risks of life-threatening SCI complications. By products of these studies are new approaches for counteracting aging muscle atrophy, new color clinical imaging of muscle tissue and Machine Learning Predictive Systems for skeletal muscle diagnostics and managements.

Human motor endplate remodeling after traumatic nerve injury

OBJECTIVECurrent management of traumatic peripheral nerve injuries is variable with operative decisions based on assumptions that irreversible degeneration of the human motor endplate (MEP) follows prolonged denervation and precludes reinnervation. However, the mechanism and time course of MEP changes after human peripheral nerve injury have not been investigated. Consequently, there are no objective measures by which to determine the probability of spontaneous recovery and the optimal timing of surgical intervention. To improve guidance for such decisions, the aim of this study was to characterize morphological changes at the human MEP following traumatic nerve injury.METHODSA prospective cohort (here analyzed retrospectively) of 18 patients with traumatic brachial plexus and axillary nerve injuries underwent biopsy of denervated muscles from the upper extremity from 3 days to 6 years after injury. Muscle specimens were processed for H & E staining and immunohistochemistry, with visualization via confocal and two-photon excitation microscopy.RESULTSImmunohistochemical analysis demonstrated varying degrees of fragmentation and acetylcholine receptor dispersion in denervated muscles. Comparison of denervated muscles at different times postinjury revealed progressively increasing degeneration. Linear regression analysis of 3D reconstructions revealed significant linear decreases in MEP volume (R = −0.92, R2 = 0.85, p = 0.001) and surface area (R = −0.75, R2 = 0.56, p = 0.032) as deltoid muscle denervation time increased. Surprisingly, innervated and structurally intact MEPs persisted in denervated muscle specimens from multiple patients 6 or more months after nerve injury, including 2 patients who had presented > 3 years after nerve injury.CONCLUSIONSThis study details novel and critically important data about the morphology and temporal sequence of events involved in human MEP degradation after traumatic nerve injuries. Surprisingly, human MEPs not only persisted, but also retained their structures beyond the assumed 6-month window for therapeutic surgical intervention based on previous clinical studies. Preoperative muscle biopsy in patients being considered for nerve transfer may be a useful prognostic tool to determine MEP viability in denervated muscle, with surviving MEPs also being targets for adjuvant therapy.