Longitudinal RNA-Seq analysis of acute and chronic neurogenic skeletal muscle atrophy.

Skeletal muscle is a highly adaptable tissue capable of changes in size, contractility, and metabolism according to functional demands. Atrophy is a decline in mass and strength caused by pathologic loss of myofibrillar proteins, and can result from disuse, aging, or denervation caused by injury or peripheral nerve disorders. We provide a high-quality longitudinal RNA-Seq dataset of skeletal muscle from a cohort of adult C57BL/6J male mice subjected to tibial nerve denervation for 0 (baseline), 1, 3, 7, 14, 30, or 90 days. Using an unbiased genomics approach to identify gene expression changes across the entire longitudinal course of muscle atrophy affords the opportunity to (1) establish acute responses to denervation, (2) detect pathways that mediate rapid loss of muscle mass within the first week after denervation, and (3) capture the molecular phenotype of chronically atrophied muscle at a stage when it is largely resistant to recovery

Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients

Background and Aims: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. Methods: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. Results: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted p-value =.0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. Interpretation: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN

Treadmill exercise induced functional recovery after peripheral nerve repair is associated with increased levels of neurotrophic factors.

Benefits of exercise on nerve regeneration and functional recovery have been reported in both central and peripheral nervous system disease models. However, underlying molecular mechanisms of enhanced regeneration and improved functional outcomes are less understood. We used a peripheral nerve regeneration model that has a good correlation between functional outcomes and number of motor axons that regenerate to evaluate the impact of treadmill exercise. In this model, the median nerve was transected and repaired while the ulnar nerve was transected and prevented from regeneration. Daily treadmill exercise resulted in faster recovery of the forelimb grip function as evaluated by grip power and inverted holding test. Daily exercise also resulted in better regeneration as evaluated by recovery of compound motor action potentials, higher number of axons in the median nerve and larger myofiber size in target muscles. Furthermore, these observations correlated with higher levels of neurotrophic factors, glial derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), in serum, nerve and muscle suggesting that increase in muscle derived neurotrophic factors may be responsible for improved regeneration

Programmed axon degeneration: from mouse to mechanism to medicine.

Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (WldS) mouse, research has generated extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of 'druggable' enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis

Effect of exercise on neurotrophic factor levels.

<p>Tissue and serum levels of GDNF, IGF-1 and BDNF were measured at 6 weeks after nerve repair. In all cases, except serum BDNF, exercised group had higher levels of all three neurotrophic factors in muscle, serum and distal nerve as measured by ELISA. Control is uninjured animals with no exercise program. Exercise and no exercise groups denote animals undergoing median nerve repair and regeneration. (* Denotes statistically significant difference compared to no-exercise group, P>0.05).</p

Effect of exercise on neurotrophic factor levels.

<p>Tissue and serum levels of GDNF, IGF-1 and BDNF were measured at 6 weeks after nerve repair. In all cases, except serum BDNF, exercised group had higher levels of all three neurotrophic factors in muscle, serum and distal nerve as measured by ELISA. Control is uninjured animals with no exercise program. Exercise and no exercise groups denote animals undergoing median nerve repair and regeneration. (* Denotes statistically significant difference compared to no-exercise group, P>0.05).</p

Effect of exercise on evoked motor response in nerve conduction study.

<p>Exercise improved both the amplitude of the evoked CMAP response (<b>A</b>) and distal latency (<b>B</b>) 6 weeks after median nerve repair. (* Denotes statistically significant difference, P>0.05).</p

Effect of exercise on functional outcomes.

<p>Exercise improved both grip strength (<b>A</b>) and time on the inverted holding test (<b>B</b>) in mice with median nerve repair over 6 weeks. (* Denotes statistically significant difference, P>0.05).</p

Effect of exercise on muscle mass.

<p>Exercise resulted in larger myofiber size as shown in (<b>B</b>) compared to uninjured control (<b>A</b>) or no-exercise group (<b>C</b>). This is quantified in (<b>D</b>). There was also a difference in total muscle weight between the exercise and no-exercise groups (<b>E</b>). (* Denotes statistically significant difference compared to no-exercise group, P>0.05).</p