Fiber Atrophy Research Articles

Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury

Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact quality of life by causing long-term disability. PNI is characterized by nerve degeneration distal to the site of nerve injury resulting in long periods of skeletal muscle denervation. During this period, muscle fibers atrophy and frequently become incapable of “accepting” innervation because of the slow speed of axon regeneration post injury. We hypothesize that reprogramming the skeletal muscle to an embryonic-like state may preserve its reinnervation capability following PNI. To this end, we generate a mouse model in which NANOG, a pluripotency-associated transcription factor is expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulates the percentage of Pax7+ nuclei and expression of eMYHC along with other genes that are involved in muscle development. In a sciatic nerve transection model, NANOG expression leads to upregulation of key genes associated with myogenesis, neurogenesis and neuromuscular junction (NMJ) formation. Further, NANOG mice demonstrate extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice show greater improvement in motor function as compared to wild-type (WT) animals, as evidenced by improved toe-spread reflex, EMG responses and isometric force production. In conclusion, we demonstrate that reprogramming muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.

Neuronal Intranuclear Inclusion Disease with a Corneal Disorder: A Case Report

Background: Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder characterized by the formation of intranuclear inclusions in cells. Adult-type NIID usually develops in elderly patients with various clinical manifestations and is sometimes accompanied by ocular symptoms. A case of adult-onset NIID with early and unique manifestations, including a progressive corneal defect and retinal changes, which are concerning at a young age, is reported. Case Presentation: A 29-year-old woman with adult sporadic NIID presented to our department with a progressive corneal disorder. Her neurological symptoms started at the age of 22 years, and she was diagnosed with NIID by skin biopsy and genetic testing. Ocular examination revealed bilateral corneal superficial punctate keratitis, right corneal opacity, decreased vision, nocturnal lagophthalmos, and early retinal changes. Corneal nerve fiber atrophy was detected by in vivo confocal microscopy. With a Cochet–Bonnet aesthesiometer, the progression of NIID and decreased corneal sensation were confirmed. Findings consistent with neurotrophic keratitis and keratoconjunctivitis due to nocturnal lagophthalmos were both suggested as being complications of her underlying NIID. Treatment with punctal plugs, sodium hyaluronate eye drops, diquafosol sodium eye drops, systemic and local antivirals, and local steroid medications resulted in the gradual improvement in the irregularity and opacity of the epithelium. Conclusions: NIID may lead to neurotrophic keratopathy due to impairment of the corneal sensory nerves. Nocturnal lagophthalmos is a remarkable finding in a case of NIID. The findings in the present case highlight the complex and multifaceted nature of NIID, with neurological and ocular manifestations requiring a multidisciplinary approach to management.

Fu-Zheng-Li-Fei Recipe (FZLFR) in the treatment of cancer cachexia: Exploration of the efficacy and molecular mechanism based on chemical characterization, experimental research and network pharmacology

Ethnopharmacological relevanceFZLFR was derived from a classic traditional Chinese medicine recipe, the Shiquan-Dabu decoction. FZLFR is commonly used in clinical practice to address muscle loss and associated cancer cachexia. However, the mechanism of by which FZLFR acts in cancer cachexia remains unclear. AimThis study aimed to assess the effects and explore the potential mechanism of action of FZLFR in treating cancer cachexia. MethodsCancer cachexia was induced by inoculating Lewis lung carcinoma cells into the right flank of male C57BL/6 mice. The efficacy of FZLFR was evaluated by comparing changes in body weight, tumor mass, food intake, survival time, weight, and cross-sectional area of the gastrocnemius and anterior tibial muscles. Moreover, inflammatory cytokines, such as TNF-α and IL-6, were detected by ELISA. The chemical components of FZLFR were analyzed using ultra-performance liquid chromatography-coupled with time-of-flight mass spectrometry. Network pharmacology analysis was performed to screen the core targets and potential pathways involved in FZLFR treatment of cancer cachexia. Molecular docking was used to analyze the binding ability of the core targets and key compounds. The expression levels of core targets and targets correlated with skeletal muscle atrophy were also assessed using western blotting. ResultsFZLFR enhanced the food intake and survival rate of mice with cancer cachexia. It also alleviated tumor-induced body weight loss, tumor growth, and muscle fiber atrophy in these mice. Additionally, it improved the weight and cross-sectional area of the gastrocnemius and anterior tibial muscles. FZLFR down-regulated the serum levels of TNF-α and IL-6. UPLC-ESI-Q-TOF-MS analysis identified 184 compounds in FZLFR. Network pharmacology analysis predicted that TNF signaling pathway, ErbB signaling pathway and VEGF signaling pathway might be essential in FZLFR action. Molecular docking showed that kaempferol, upafolin, apigenin, and luteolin might play key roles in FZLFR treatment. Moreover, FZLFR decreased MAFBx1, MURF1, NF-κB, TWEAK, MAPK8, and EGFR expression levels. FZLFR enhanced the expression of VEGFA and ESR1, as demonstrated by western blotting. ConclusionsFZLFR increased food intake and alleviated muscle atrophy in mice with cancer cachexia. The potential pharmacological mechanisms underlying its anticachexia effects include reducing inflammation, enhancing muscle vascular growth, inhibiting tumor angiogenesis, and modulating estrogen receptors.

Prevalence and identification of cyathocotylid trematodes infecting African catfish in Egypt.

The trematode family Cyathocotylidae infects various hosts worldwide, including birds, mammals, reptiles, and fish. However, the lack of molecular data from adult worms hinders phylogenetic, epidemiological, and host association studies. This study aims to identify the common cyathocotylid trematodes infecting African catfish in Egypt using morphological and molecular evidence. Out of 142Clarias gariepinus, 123 fish (86.6%) harbored cyathocotylid metacercariae, with a mean metacercarial intensity of 201 ± 38.5/g. Cyathocotylid metacercariae prevalence gradually rose as host size increased. Although there was no significant difference between groups, larger fish had a higher mean metacercarial intensity. The prevalence and intensity were unrelated to the fish gender. Histopathological examination of metacercariae-infected catfish revealed varying degrees of degenerative changes, including intermuscular edema leading to muscle fiber dispersion and atrophy, involving 11% to over 81% of muscle sections. We identified three cyathocotylid metacercariae and eight cyathocotylid adult species from experimental infection using morphometric and molecular data, including internal transcribed spacer (ITS) and/or mitochondrial cytochrome c oxidase subunit 1 (cox1) sequences. We determined the phylogenetic position of these cyathocotylid samples.The ITS sequence analysis linked the isolated Cyathocotylidae sp. 1 and 2 metacercariae to Prohemistomum vivax adults. Mesostephanus appendiculatoides and Paracoenogonimus ovatus were reported for the first time in Egypt. These findings may provide valuable genetic data for future molecular epidemiological and phylogenetic studies of cyathocotylid trematodes.

The therapeutic potential of red beetroot (Beta vulgaris L.) intake on muscle atrophy in immobilized mouse skeletal muscles

AbstractSkeletal muscle atrophy is the reduction in muscle mass and function caused by an imbalance in protein synthesis and degradation. Inflammation has been shown to accelerate protein degradation during periods of muscle inactivity. We investigated the potential therapeutic effects of beetroot extract (BRE) in reducing inflammation and oxidative stress to prevent muscular atrophy after a short period of immobilization. We divided 36 male BALB/c mice into three groups: control, muscular atrophy mice, and muscular atrophy mice treated with BRE (n = 12). Each group was further divided into two subgroups: (1) 7‐day immobilization and (2) 10‐day recovery. BRE was administered orally at a dose of 300 mg/kg for 17 days. We assessed the anti‐inflammatory and antioxidative effects of BRE using ELISA and RT‐PCR assays. Hematoxylin–eosin staining was used to measure the cross‐sectional area (CSA) of muscle fibers, and grip strength tests were performed to assess muscle strength. BRE administration increased muscle weight, CSA, and grip strength in mice with immobilization‐induced muscle atrophy. It also suppressed inflammation and oxidative stress biomarkers in atrophic muscle fibers. Higher nitrate levels and lower Troponin I (TnI) concentrations were observed in the BRE‐treated group, indicating improved muscle function and structure. These findings suggest that BRE may have therapeutic benefits in improving muscle mass and function and warrant further studies in humans, particularly in individuals with low physical activity levels.

BMSCs-Derived Extracellular VesiclemiR-29a-3p Improved the Stability of Rat Myasthenia Gravis by Regulating Treg/Th17 Cells

ABSTRACT Introduction Myasthenia gravis (MG) is an autoimmune disorder. Microvesicle-derived miRNAs have been implicated in autoimmune diseases. However, the role of microvesicle-derived miR-29a-3p in MG remains poorly understood. This study aimed to investigate the therapeutic effect and mechanism of miR-29a-3p derived from stem cell microvesicles (MVs) on experimental autoimmune myasthenia gravis (EAMG) rats. Methods EAMG was induced in rats by injection of the subunit of the rat nicotinic anti-acetylcholine receptor (AChR) R97–116 peptide.Besides the control group, EAMG rats were randomly allocated into the EAMG model group, MV group, MV-NC-agomir group, and MV- miR-29a-3p-agomir group. Results Our results found that BMSCs-MV promoted miR-29a-3p expression in gastrocnemius of EAMG rats. Bone marrow mesenchymal stem cells (BMSCs) derived microvesicle miR-29a-3p improved the hanging ability and swimming time of EMGA rats and weakened the degree of muscle fiber atrophy. Furthermore, microvesicles from miR-29a-3p overexpressing BMSCs reduced the content of AchR-Ab in the serum of EAMG rats. BMSC-derived microvesicle miR-29a-3p further suppressed the expression of IFN-γ and enhanced the IL-4 and IL-10 in the serum of EAMG rats by restoring the Th17/Treg cells balance. Discussion BMSCs-derived microvesicle miR-29a-3p improved the stability of rat myasthenia gravis by regulating Treg/Th17 cells. It may be an effective treatment for MG.

From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders.

Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), primarily affect the central nervous system, leading to progressive neuronal loss and motor and cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe muscle wasting as a result of motor neuron degeneration, as well as alterations in gene expression, protein aggregation, and oxidative stress. Muscle atrophy and mitochondrial dysfunction are also observed in AD, which may exacerbate cognitive decline due to systemic metabolic dysregulation. PD patients exhibit muscle fiber atrophy, altered muscle composition, and α-synuclein aggregation within muscle cells, contributing to motor symptoms and disease progression. Systemic inflammation and impaired protein degradation pathways are common among these disorders, highlighting muscle tissue as a key player in disease progression. Understanding these muscle-related changes offers potential therapeutic avenues, such as targeting mitochondrial function, reducing inflammation, and promoting muscle regeneration with exercise and pharmacological interventions. This review emphasizes the importance of considering an integrative approach to neurodegenerative disease research, considering both central and peripheral pathological mechanisms, in order to develop more effective treatments and improve patient outcomes.

PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection.

Intensive care unit-acquired weakness (ICU-AW) is prevalent in critical care, with limited treatment options. Certain microRNAs, like miR-542, are highly expressed in ICU-AW patients. This study investigates the regulatory role and mechanisms of miR-542 in ICU-AW and explores the clinical potential of miR-542 inhibitors. ICU-AW models were established in C57BL/6 mice through cecal ligation and puncture (CLP) and in mouse C2C12 myoblasts through TNF-α treatment. In vivo experiments demonstrated decreased muscle strength, muscle fiber atrophy, widened intercellular spaces, and increased miR-542-3p/5p expression in ICU-AW mice model. In vitro experiments indicated suppressed ATG5, ATG7 and LC3II/I, elevated MDA and ROS levels, decreased SOD levels, and reduced MMP in the model group. Similar to animal experiments, the expression of miR-542-3p/5p was upregulated. Gel electrophoresis explored the binding of polyethyleneimine/mesoporous silica nanoparticles (PEI/MMNs) to locked nucleic acid (LNA) miR-542 inhibitor (LNA-542). PEI/MMNs@LNA-542 with positive charge (3.03 ± 0.363 mV) and narrow size (206.94 ± 6.19 nm) were characterized. Immunofluorescence indicated significant internalization with no apparent cytotoxicity. Biological activity, examined through intraperitoneal injection, showed that PEI/MMNs@LNA-542 alleviated muscle strength decline, restored fiber damage, and recovered mitochondrial injury in mice. In conclusion, PEI/MMNs nanoparticles effectively delivered LNA-542, targeting ATG5 to inhibit autophagy and alleviate mitochondrial damage, thereby improving ICU-AW.

Long-term effects of the chronic administration of doxorubicin on aged skeletal muscle: An exploratory study in mice

The widely used chemotherapeutic drug doxorubicin (DOX) has been associated with adverse effects on the skeletal muscle, which can persist for years after the end of the treatment. These adverse effects may be exacerbated in older patients, whose skeletal muscle might already be impaired by aging. Nonetheless, the mediators responsible for DOX-induced myotoxicity are still largely unidentified, particularly the ones involved in the long-term effects that negatively affect the quality of life of the patients. Therefore, this study aimed to investigate the long-term effects of the chronic administration of DOX on the soleus muscle of aged mice. For that and to mimic the clinical regimen, a dose of 1.5 mg kg−1 of DOX was administered two times per week for three consecutive weeks in a cumulative dose of 9 mg kg−1 to 19-month-old male mice, which were sacrificed two months after the last administration. Body wasting and the atrophy of the soleus muscle, as measured by a decrease in the cross-sectional area of the soleus muscle fibers, were identified as long-term effects of DOX administration. The atrophy observed was correlated with increased reactive oxygen species production and caspase-3 activity. An impaired skeletal muscle regeneration was also suggested due to the correlation between satellite cells activation and the soleus muscle fibers atrophy. Systemic inflammation, skeletal muscle energy metabolism and neuromuscular junction-related markers do not appear to be involved in the long-term DOX-induced skeletal muscle atrophy. The data provided by this study shed light on the mediators involved in the overlooked long-term DOX-induced myotoxicity, paving the way to the improvement of the quality of life and survival rates of older cancer patients.

Amyotrophic lateral sclerosis as a disease model of sarcopenia

Abstract Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.

Chikungunya and Mayaro Viruses Induce Chronic Skeletal Muscle Atrophy Triggered by Pro-Inflammatory and Oxidative Response.

Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, nuclear magnetic resonance imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced inflammation promote a rapid loss of muscle mass and reduction in fiber cross-sectional area by upregulation of muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 expression, both key regulators of SkM fibers atrophy. Despite a reduction in inflammation and clearance of infectious viral particles, SkM atrophy persists until 30 days post-infection. The genomic CHIKV and MAYV RNAs were still detected in SkM in the late phase, along with the upregulation of chemokines and anti-inflammatory cytokine expression. In agreement with the involvement of inflammatory mediators on induced atrophy, the neutralization of TNF and a reduction in oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogen expression and atrophic fibers while increasing weight gain in treated mice. These data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphavirus pathogenesis and with a description of potentially new targets of therapeutic intervention.

Association analysis of indel variants and gene expression identifies MDM4 as a novel locus for skeletal muscle hypertrophy and power athlete status.

Insertions and deletions (indels) are the second most common type of variation in the human genome. However, limited data on their associations with exercise-related phenotypes have been documented. The aim of the present study was to examine the association between 18,370 indel variants and power athlete status, followed by additional studies in 357,246 individuals. In the discovery phase, the D allele of the MDM4 gene rs35493922 I/D polymorphism was over-represented in power athletes compared with control subjects (P=7.8×10-9) and endurance athletes (P=0.0012). These findings were replicated in independent cohorts, showing a higher D allele frequency in power athletes compared with control subjects (P=0.016) and endurance athletes (P=0.031). Furthermore, the D allele was positively associated (P=0.0013) with greater fat-free mass in the UK Biobank. MDM4 encodes a protein that inhibits the activity of p53, which induces muscle fibre atrophy. Accordingly, we found that MDM4 expression was significantly higher in the vastus lateralis of power athletes compared with endurance athletes (P=0.0009) and was positively correlated with the percentage of fast-twitch muscle fibres (P=0.0062) and the relative area occupied by fast-twitch muscle fibres (P=0.0086). The association between MDM4 gene expression and an increased proportion of fast-twitch muscle fibres was confirmed in two additional cohorts. Finally, we found that the MDM4 DD genotype was associated with increased MDM4 gene expression in vastus lateralis and greater cross-sectional area of fast-twitch muscle fibres. In conclusion, MDM4 is suggested to be a potential regulator of muscle fibre specification and size, with its indel variant being associated with power athlete status. HIGHLIGHTS: What is the central question of this study? Which indel variants are functional and associated with sport- and exercise-related traits? What is the main finding and its importance? Out of 18,370 tested indels, the MDM4 gene rs35493922 I/D polymorphism was found to be the functional variant (affecting gene expression) and the most significant, with the deletion allele showing associations with power athlete status, fat-free mass and cross-sectional area of fast-twitch muscle fibres. Furthermore, the expression of MDM4 was positively correlated with the percentage of fast-twitch muscle fibres and the relative area occupied by fast-twitch muscle fibres.

Identification of Genomic Predictors of Muscle Fiber Size.

The greater muscle fiber cross-sectional area (CSA) is associated with greater skeletal muscle mass and strength, whereas muscle fiber atrophy is considered a major feature of sarcopenia. Muscle fiber size is a polygenic trait influenced by both environmental and genetic factors. However, the genetic variants underlying inter-individual differences in muscle fiber size remain largely unknown. The aim of our study was to determine whether 1535 genetic variants previously identified in a genome-wide association study of appendicular lean mass are associated with the CSA of fast-twitch muscle fibers (which better predict muscle strength) in the m. vastus lateralis of 148 physically active individuals (19 power-trained and 28 endurance-trained females, age 28.0 ± 1.1; 28 power-trained and 73 endurance-trained males, age 31.1 ± 0.8). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified as having an association with muscle fiber size (p < 0.05). Of these 57 SNPs, 31 variants were also associated with handgrip strength in the UK Biobank cohort (n = 359,729). Furthermore, using East Asian and East European athletic (n = 731) and non-athletic (n = 515) cohorts, we identified 16 SNPs associated with athlete statuses (sprinter, wrestler, strength, and speed-strength athlete) and weightlifting performance. All SNPs had the same direction of association, i.e., the lean mass-increasing allele was positively associated with the CSA of muscle fibers, handgrip strength, weightlifting performance, and power athlete status. In conclusion, we identified 57 genetic variants associated with both appendicular lean mass and fast-twitch muscle fiber size of m. vastus lateralis that may, in part, contribute to a greater predisposition to power sports.

Diffusion-tensor magnetic resonance imaging as a non-invasive assessment of extracellular matrix remodeling in lumbar paravertebral muscles of rats with sarcopenia

BackgroundExtracellular matrix (ECM) remodeling in skeletal muscle is a significant factor in the development of sarcopenia. This study aims to evaluate changes in ECM remodeling in the lumbar paravertebral muscles of sarcopenic rats using diffusion-tensor magnetic resonance imaging (DT-MRI) and compare them with histology.MethodsTwenty 6-month-old female Sprague Dawley rats were randomly divided into the dexamethasone (DEX) group and the control (CON) group. Both groups underwent 3.0T MRI scanning, including Mensa, T2WI, and DT-MRI sequences. The changes in muscle fibers and extracellular matrix (ECM) of the erector spinal muscle were observed using hematoxylineosin and sirius red staining. The expressions of collagen I, III, and fibronectin in the erector spinae were detected by western blot. Pearson correlation analysis was employed to assess the correlation between MRI quantitative parameters and corresponding histopathology markers.ResultsThe cross-sectional area and fractional anisotropy values of the erector spinae in the DEX group rats were significantly lower than those in the CON group (p < 0.05). Hematoxylin eosin staining revealed muscle fiber atrophy and disordered arrangement in the DEX group, while sirius red staining showed a significant increase in collagen volume fraction in the DEX group. The western blot results indicate a significant increase in the expression of collagen I, collagen III, and fibronectin in the DEX group (p < 0.001 for all). Correlation coefficients between fractional anisotropy values and collagen volume fraction, collagen I, collagen III, and fibronectin were − 0.71, -0.94, -0.85, and − 0.88, respectively (p < 0.05 for all).ConclusionsThe fractional anisotropy value is strongly correlated with the pathological collagen volume fraction, collagen I, collagen III, and fibronectin. This indicates that DT-MRI can non-invasively evaluate the changes in extracellular matrix remodeling in the erector spinal muscle of sarcopenia. It provides a potential imaging biomarker for the diagnosis of sarcopenia.

Skeletal muscle involvement in systemic amyloidosis is often overlooked.

Systemic amyloidosis is a condition in which misfolded amyloid fibrils are deposited within tissues. Amyloid myopathy is a rare manifestation of systemic amyloidosis. However, whether skeletal muscle involvement is underestimated and whether such deposition guarantees clinical and pathological myopathic features remain to be investigated. We retrospectively reviewed patients with systemic amyloidosis, in whom skeletal muscle biopsies were performed at our centre between January 2018 and June 2023. In total, 28 patients with suspected systemic amyloidosis were included. Among these, 21 presented with cardiomyopathy but lacked myopathic symptoms. The clinical and pathological data of these patients were further analysed. The amyloid type was confirmed by immunohistochemistry. Twenty-eight patients with suspected systemic amyloidosis underwent muscle biopsy. Amyloid deposition in the skeletal muscle was confirmed in 24 patients, including 22 with light-chain amyloidosis (AL) and two with transthyretin amyloidosis (ATTR). Among the 24 patients, seven presented with muscle weakness and decreased muscle strength (Group 1, symptomatic myopathy), whereas the remaining 17 exhibited normal muscle strength (Group 2, asymptomatic myopathy). Group 1 included four patients with AL-λ, one with AL-κ and two with ATTR. Group 2 included 15 patients with AL-λ and two patients with AL-κ. In Group 1, six patients exhibited neuropathy, whereas only one patient in Group 2 presented with subclinical neuropathy on nerve conduction studies. Amyloid deposition in the interstitium was the most obvious change, observed in all 24 patients. Neuropathic changes, including denervation atrophy and muscle fibre grouping, were also common. Except for type 2 fibre atrophy, the other myopathic changes were mild and nonspecific. No sarcolemmal disruption was observed. Immunohistochemical analysis revealed marked positivity for MAC and MHC1 expression in the regions with amyloid deposits. Clinicopathological analysis revealed no significant differences in the extent of muscular amyloid deposition between the two groups. Nevertheless, patients in Group 1 displayed more pronounced neurogenic atrophy on skeletal muscle biopsies. Our study indicates that amyloid deposition in skeletal muscle is commonly observed but rarely causes symptomatic myopathy in systemic amyloidosis.

Compound Muscle Action Potential and Myosin-Loss Pathology in Patients With Critical Illness Myopathy: Correlation and Prognostication.

Prolonged compound muscle action potential (CMAP) duration and preferential loss of myosin are considered the diagnostic hallmarks of critical illness myopathy (CIM); however, their correlation and prognostic values have not been studied. We aimed to investigate the correlation between CMAP duration and myosin loss and their effect on mortality by comparing between patients with CIM with and without myosin loss. We searched the Mayo Clinic Electromyography Laboratory databases (1986-2021) for patients diagnosed with CIM on the basis of prolonged distal CMAP durations (>15 msec in fibular motor nerve studies recording over the tibialis anterior or >8 msec in other motor nerves) and needle EMG findings compatible with myopathy. Electrodiagnostic studies were generally performed within 24 hours after weakness became noticeable. We included only patients who underwent muscle biopsy. Clinical, electrophysiologic, and myopathologic data were reviewed. We conducted myosin/actin ratio analysis when muscle tissue was available. We used the Fisher exact test for categorical data comparisons and the Mann-Whitney 2-tailed test for continuous data. We applied the Kaplan-Meier technique to analyze survival rates. Twenty patients (13 female patients) were identified [median age at diagnosis of 62.5 years (range: 19-80 years)]. The median onset of weakness was 24 days (range: 1-128) from the first day of intensive care unit admission. Muscle biopsy showed myosin loss in 14 patients, 9 of whom had >50% of myofibers affected (high grade). Type 2 fiber atrophy was observed in 19 patients, 13 of whom also had myosin loss. Patients with myosin loss had higher frequency of steroid exposure (14 vs 3; p = 0.004); higher median number of necrotic fibers per low-power field (2.5 vs 1, p = 0.04); and longer median CMAP duration (msec) of fibular (13.4 vs 8.75, p = 0.02), tibial (10 vs 7.8, p = 0.01), and ulnar (11.1 vs 7.95, p = 0.002) nerves compared with those without. Only patients with high-grade myosin loss had reduced myosin/actin ratios (<1.7). Ten patients died during median follow-up of 3 months. The mortality rate was similar between patients with and without myosin loss. Patients with high-grade myosin loss had a lower overall survival rate than those with low-grade or no myosin loss, but this was not statistically significant (p = 0.05). Myosin loss occurred in 70% of the patients with CIM with prolonged CMAP duration. Longer CMAP duration predicts myosin-loss pathology. The extent of myosin loss marginally correlates with the mortality rate. Our findings highlight the potential prognostic values of CMAP duration and myosin loss severity in predicting disease outcome.

Stroke-induced excess in capillarization relative to oxidative capacity in rats is muscle specific.

Stroke is not only associated with muscle weakness, but also associated with reduced muscle fatigue resistance and reduced desaturation during exercise that may be caused by a reduced oxidative capacity and/or microvasculature. Therefore, the objective of the present study was to determine the effects of stroke on muscle mass, fiber size and shape, capillarization and oxidative capacity of the rat m. extensor carpi radialis (ECR) and m. flexor carpi ulnaris (FCU) after a photothrombotic stroke in the forelimb region of the primary sensorimotor cortex. The main observation of the present study was that 4 weeks after induction of stroke there were no significant changes in muscle fiber size and shape. Although there was no significant capillary rarefaction, there was some evidence for remodeling of the capillary bed as reflected by a reduced heterogeneity of capillary spacing (p = 0.006) that may result in improved muscle oxygenation. In the ECR, but not in the FCU, this was accompanied by reduction in muscle fiber oxidative capacity as reflected by reduced optical density of sections stained for succinate dehydrogenase (p = 0.013). The reduced oxidative capacity and absence of significant capillary rarefaction resulted in a capillary to fiber ratio per unit of oxidative capacity that was higher after stroke in the ECR (p = 0.01), but not in the FCU. This suggests that at least during the early stages, stroke is not necessarily accompanied by muscle fiber atrophy, and that stroke-induced reductions in oxidative capacity resulting in relative excess of capillarization are muscle specific.

A Rare Case of Neuronal Ceroid Lipofuscinosis-Type 1 (NCL-1) with Vitamin D-Dependent Rickets-Type 1 (VDDR-1), Complex 1 Mitochondrial Deficiency, and Mixed Variant-Checkerboard and Phylloid Type of Pigmentary Mosaicism.

Introduction Neuronal ceroid lipofuscinosis-type 1 (NCL-1) is a neurodegenerative lysosomal storage disorder. Vitamin D-dependent rickets type 1 (VDDR-1) is a rare cause of refractory rickets. Here, we report an unusual association of NCL-1 with VDDR-1. Case A 3-year-old boy presented with a history of seizures from 45 days of life, delayed development, and loss of attained milestones at 20 months of age, along with progressive vision impairment since 1 year. Examination showed a failure to thrive, microcephaly, rachitic rosary, checkerboard and phylloid type of pigmentary mosaicism, fundus showed disc pallor with generalized narrowing of arterioles, bilateral retinitis pigmentosa, spasticity and dystonia, brisk reflexes, extensor plantar, and left choreoathetoid movements. Investigations showed hypocalcemia (7.8 mg/dL), normal phosphorus (3.9 mg/dL), elevated alkaline phosphatase (508.8 U/L), elevated parathyroid hormone (513.35 pg/mL), low 1,25-dihydroxy-vitamin D (9.93 pg/mL), and normal renal function. The child had metabolic acidosis, elevated ammonia (403.9 micromol/L), lactate (95 mg/dL, normal range 4.5-19.8 mg/dL), and creatine phosphokinase (432 U/L) level, and normal tandem mass spectroscopy. X-ray wrist showed healing vitamin deficiency rickets. Abnormal electroencephalogram was suggestive of low voltage activity. Magnetic resonance imaging brain showed gross cerebral and cerebellar atrophy. A muscle biopsy showed scattered atrophic fibers and several ultrastructural granular osmiophilic deposits and some mitochondrial aggregates of varying size were observed. Mitochondrial respiratory chain enzyme assay exhibited complex-1 deficiency (activity < 30%). Genetic analysis showed two pathogenic mutations: homozygous nonsynonymous variation c.674T > C in exon 7 of the PPT1 gene and a homozygous frameshift variation c.1178_1179delAA in exon 7 of CYP27B1 confirming the diagnosis of NCL-1 with VDDR-1. The child was treated with a low protein diet, levetiracetam, clonazepam, trihexyphenidyl, haloperidol, calcium supplement, calcitriol, and sodium benzoate; some improvement in clinical and biochemical parameters was noted on follow-up. Conclusion This is a novel association of NCL-1 with VDDR-1 associated with complex-1 mitochondrial deficiency which has previously not been reported in the literature.

Isolation, Characterization, and Pathogenicity of an Aeromonas veronii Strain Causing Disease in Rhinogobio ventralis

Rhinogobio ventralis is a rare fish found in the Yangtze River in China and has significant ecological and economic value. In this study, a bacterial strain (RV-JZ01) was isolated from the livers of diseased R. ventralis. This isolate was identified as Aeromonas veronii based on its morphology, biochemical features and 16S rDNA phylogenetic analysis. The artificial infection of healthy R. ventralis (16 ± 2 cm) with RV-JZ01 resulted in the manifestation of clinical symptoms, in accordance with those of naturally infected fish. The 50% lethal dose (LD50) of RV-JZ01 for R. ventralis was 6.3 × 106 CFU/mL. Histopathological examination revealed various pathological changes in the diseased fish, including intestinal villus swelling and rupture, hepatocyte vacuolization, renal tubular cell nuclear enlargement and pyknosis, and myocardial fiber fracture and atrophy. RV-JZ01 infection significantly reduced the gut flora diversity of R. ventralis, with the relative abundances of Firmicutes and Fusobacteria increasing, and those of the Proteobacteria and Bacteroidetes decreasing. The abundance of Lactobacillus and Streptococcus dramatically increased, and the abundance of Clostridium and Escherichia reduced in the intestinal microbiota of R. ventralis infected with RV-JZ01. Antibiotic sensitivity testing revealed that RV-JZ01 was highly susceptible to 12 antimicrobials, including erythromycin, cefalexin, norfloxacin, furazolidone, sulfonamides, enrofloxacin, doxycycline, piperacillin, florfenicol, gentamicin, and lincomycin. These results contribute to the understanding of pathological alterations in R. ventralis following A. veronii infection, offering valuable data to support the implementation of disease treatment.

Clinical features and genetic analysis of a child with Central core disease due to compound heterozygous variants of RYR1 gene

To explore the clinical features and genetic etiology of a child with Central core disease (CCD). A child with CCD who was treated at the Children's Hematology Department of the First Affiliated Hospital of Zhengzhou University in February 2022 was selected as the study subject. Muscle biopsy was performed. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The child, a 12-year-old boy, had manifested motor retardation, facial weakness, ptosis, pectus carinatum, scoliosis, etc. Muscle biopsy showed that the central nucleus muscle fibers and atrophic muscle fibers were mainly type I. WES revealed that the child has harbored c.10561G>A (p.G3521S) and c.3448T>C (p.C1150R) compound heterozygous variants of the RYR1 gene. Sanger sequencing confirmed that they were inherited from his mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were considered as likely pathogenic (PS4+PM1+PM2_Supporting+PP3；PM1+PM2_Supporting+PM3+PP3). By combining his clinical manifestation and results of muscle pathology and genetic testing, the child was diagnosed with CCD, which may be attributed to the c.10561G>A (p.G3521S) and c.3448T>C (p.C1150R) compound heterozygous variants of the RYR1 gene.