Muscle Degeneration Research Articles

Paraspinal Muscle Morphology in Proximal Cervical Spondylotic Amyotrophy.

This is a retrospective analysis of prospectively collected single-center observational data. The aim is to evaluate atrophy and fatty degeneration rates of cervical spinal muscles in proximal cervical spondylotic amyotrophy (PCSA). Proximal cervical spondylotic amyotrophy affects muscles in the upper extremities. In cases that lack improvement with conservative treatment, surgery is recommended. However, preoperative factors associated with poor outcomes remain unclear. We hypothesized that assessing fatty degeneration of the cervical spinal muscles and examining its relationship with functional impairment would help predict postoperative improvement in neurological function. This study included 18 patients who underwent PCSA surgery. We performed selective laminoplasty and foraminotomy. Preoperative paraspinal muscle cross-sectional area and fatty degeneration were quantified and correlated with neurological function. Neurological improvement based on manual muscle testing was observed in 12/18 patients, comparing preoperative, perioperative, and over 12-month postoperative statuses. On the affected side, at the C4/5 level, fatty degeneration was more significant in the trapezius, whereas at the C5/6 level, fatty degeneration was more significant in the splenius capitis and trapezius. The fatty degeneration of the C4/5 and C5/6 trapezius was significantly correlated with preoperative muscle strength and postoperative muscle strength improvement. The degree of fat infiltration of the muscle correlated with pre- and postoperative muscle strength at the lesion level. Thus, our results suggest a relationship between cervical muscle morphology and the clinical manifestations of PCSA. The marked increase in trapezius fatty infiltration at the C4/5 and C5/6 levels may be a valuable indicator to predict poor improvements in postoperative muscle strength.

Single cell RNA sequencing of human FAPs reveals different functional stages in Duchenne muscular dystrophy.

Background: Duchenne muscular dystrophy is a genetic disease produced by mutations in the dystrophin gene characterized by early onset muscle weakness leading to severe and irreversible disability. Muscle degeneration involves a complex interplay between multiple cell lineages spatially located within areas of damage, termed the degenerative niche, including inflammatory cells, satellite cells (SCs) and fibro-adipogenic precursor cells (FAPs). FAPs are mesenchymal stem cell which have a pivotal role in muscle homeostasis as they can either promote muscle regeneration or contribute to muscle degeneration by expanding fibrotic and fatty tissue. Although it has been described that FAPs could have a different behavior in DMD patients than in healthy controls, the molecular pathways regulating their function as well as their gene expression profile are unknown. Methods: We used single-cell RNA sequencing (scRNAseq) with 10X Genomics and Illumina technology to elucidate the differences in the transcriptional profile of isolated FAPs from healthy and DMD patients. Results: Gene signatures in FAPs from both groups revealed transcriptional differences. Seurat analysis categorized cell clusters as proliferative FAPs, regulatory FAPs, inflammatory FAPs, and myofibroblasts. Differentially expressed genes (DEGs) between healthy and DMD FAPs included upregulated genes CHI3L1, EFEMP1, MFAP5, and TGFBR2 in DMD. Functional analysis highlighted distinctions in system development, wound healing, and cytoskeletal organization in control FAPs, while extracellular organization, degradation, and collagen degradation were upregulated in DMD FAPs. Validation of DEGs in additional samples (n = 9) using qPCR reinforced the specific impact of pathological settings on FAP heterogeneity, reflecting their distinct contribution to fibro or fatty degeneration in vivo. Conclusion: Using the single-cell RNA seq from human samples provide new opportunities to study cellular coordination to further understand the regulation of muscle homeostasis and degeneration that occurs in muscular dystrophies.

Effects of N-acetylcysteine on sciatic nerve healing: A histopathological, functional, and biochemical study of the rat sciatic nerve.

This study aims to evaluate the histopathological, biochemical, and functional effects of N-acetylcysteine (NAC), which has antioxidant, anti-inflammatory, and cytoprotective activity, on nerve regeneration in rats with sciatic nerve crush (axonotmesis) injury. This study used 16 male Wistar rats, which were divided into treatment and control groups. A standard axonotmesis-type surgical injury was induced in the left sciatic nerves of all rats. The treatment group was given 300 mg/kg of intraperitoneal NAC once a day, whereas the control group received an equal volume of saline solution. After conducting gait analyses, the sciatic functional index (SFI) was used for functional assessment. After gait analysis, all animals were euthanized. Blood samples were examined biochemically. The left sciatic nerves and left triceps surae muscles were examined histopathologically. Histopathologically, the thickness of the perineurium, axonal degeneration, axonolysis, edema, inflammation, muscle atrophy, and muscle degeneration were all significantly lower in the treatment group (p<0.05). Functionally, SFI-1, SFI-2, and SFI-3 were significantly higher in the treatment group (p<0.05). Biochemically, while the native thiol level and native thiol/total thiol ratio were significantly higher in the treatment group (p<0.003), the disulfide/total thiol ratio was significantly higher in the control group (p<0.005). Significant correlations were found between six of the seven gait parameters and the histopathological findings (p<0.05). Our study results suggest that NAC may contribute positively to the histopathological and functional recovery of sciatic nerve injury in rats. Furthermore, NAC may have an antioxidant effect on thiol-disulfide homeostasis at a biochemical level. We believe that NAC has a stimulatory effect on healing following nerve injuries.

Recovery of muscular tissue and functional results of patients treated with a gluteus maximus flap transfer due to chronic abductor deficiency after total hip arthroplasty.

To evaluate the function of the abductor mechanism after a gluteus maximus flap transfer due to a degeneration of the muscles after hip arthroplasty, we analyzed the post-operative functional outcome as well as radiographic effects in muscle tissue. This present study included six consecutive patients operatively treated with a gluteus maximus flap due to chronic gluteal deficiency after total hip arthroplasty. All patients presented a preoperative severe limp, hip abductor deficiency and a history of conservative treatment without the relief of symptoms. MRI scans were performed pre- and postoperatively to evaluate the muscle volume and grade of degeneration of the abductor mechanism. For clinical evaluation, the Harris hip score (HHS) was applied pre- and postoperatively. Moreover, the intensity of pain, the Trendelenburg sign, the internal rotation lag sign and the abductor muscle force were measured before and after surgery. Overall, the evaluation of the Magnetic Resonance Imaging (MRI) showed no significant changes in total muscle volume during the follow-up period. Separate measurements presented a significant growth of muscle volume for the gluteus minimus and tensor fascia lata compared to preoperative imaging during the follow-up period. The amount of fat volume decreased for all the measured muscles with statistical significance for the gluteus minimus, the gluteus medius and the tensor fascia lata. No further muscle degeneration and no flap necrosis were measured. The postoperative HHS results were not statistically significant compared to the preoperative results. Besides fair clinical results, the radiological measurements indicate that the flap transfer enables functional muscular tissue recovery and prevents further degeneration. Given these conditions, the gluteus maximus muscle flap transfer represents a viable treatment option for patients with chronic gluteal deficiency in selected patients.

Does surgical intervention alter the natural history of degenerative rotator cuff tears? Comparative analysis from a prospective longitudinal study

The natural history of rotator cuff tears often involves progressive pain development, tear enlargement, and advancing muscle fatty degeneration. Both surgery and conservative management have proven to be effective treatments. Our study purpose was to compare the short to mid-term effects of rotator cuff repair on shoulder function, progression of tear size, and muscle degeneration compared to controls with asymptomatic tears that developed pain and were managed nonoperatively. This comparative study consists of two separate longitudinal study arms. The control group consisted of asymptomatic degenerative cuff tears followed until pain development and then managed nonoperatively with continued surveillance. The surgical group consisted of subjects with degenerative tears that failed nonoperative treatment and underwent surgical intervention with a minimum of 2 years follow-up. Outcomes included VAS pain, ASES, AROM, strength, and ultrasonography. There were 83 controls and 65 surgical shoulders. The surgical group was younger at enrollment (58.9±5.3 yr vs. 61.2±7.8 yr, p=0.04). The median follow-up for control subjects after pain development was 5.1 years (IQR 3.6) and the median postoperative follow-up for the surgical group was 3.0 years (IQR 0.2). Baseline tear widths (median 14 mm, IQR 9 vs. 13 mm, IQR 8; p=0.45) and tear lengths (median 14 mm, IQR 13 vs. median 11 mm, IQR 8; p=0.06) were similar between the surgical group and controls. There were no differences in the baseline prevalence of fatty degeneration of the supraspinatus or infraspinatus muscles between groups (p=0.43 and p=0.58, respectively). At final follow-up, the surgical group demonstrated significantly lower VAS pain (0 [IQR 2] vs. 3.5 [IQR 4], p=0.0002), higher composite ASES (95 [IQR 13] vs. 65.8 [IQR 32], p=0.0002) and ADL scores (29 [IQR 4] vs. 22 [IQR 8], p=0.0002), greater abduction strength (69.6 N [SD 29] vs. 35.9 N [SD 29], p=0.0002), greater active forward elevation (155˚ [SD 8] vs. 142˚ [SD 28], p=0.002), greater active external rotation in abduction (mean 98.5˚, SD 12 vs. mean 78.2˚, SD 20; p=0.0002) compared to controls. Additionally, the prevalence of fatty muscle degeneration was lower in the surgical group for the supraspinatus and infraspinatus (25% vs. 41%, p=0.05; 17% vs. 34%, p=0.03; respectively). This prospective longitudinal study comparing a surgical cohort undergoing rotator cuff repair with a control group treated nonoperatively supports the notion that surgical intervention has the potential to alter the early natural history of degenerative rotator cuff disease. Patients in the surgical group demonstrated clinically relevant differences in pain and functional outcomes. Surgical intervention was protective against progressive muscle degeneration compared to nonoperative treatment.

Impact of Hyperhomocysteinemia on Cytokine and Matrix Metalloproteinases Contents in Rat Skeletal Muscle

Abstract Background: High levels of homocysteine (Hcy) in the blood (hyperhomocysteinemia [HHcy]) are associated with many pathologies, including atherosclerosis, coronary heart disease, stroke, neurological disorders, and a decrease in muscle mass and strength. The present study aimed to evaluate the levels of pro- and anti-inflammatory cytokines and matrix metalloproteinases (MMPs) in skeletal muscle of rats with experimental HHcy. Methods: HHcy in rats of two age groups was induced by intragastric administration of D, L-thiolactone Hcy for 8 weeks. The criterion for the development of pathological conditions was a blood Hcy level above 15 mmol L−1. Cytokine and MMP levels in muscle homogenate were determined by enzyme-linked immunosorbent assay. Results: The findings of the study on the content of pro-inflammatory cytokines in skeletal muscles of rats with hyperhomocysteinemia indicated the following. For immature rats, the greatest reduction in tumor necrosis factor-α and interleukin-8 (IL-8) content was observed, whereas, for mature individuals, the most pronounced decline in IL-1b was evident in skeletal muscle tissue under the pathology state. The content of anti-inflammatory interferon-γ was also reduced in the muscles of both age groups by 30% compared to the control, besides a decrease in the content of collagenase MMP-1 was also observed. Conclusions: The presence of HHcy is associated with metabolic changes in skeletal muscles, which can result in a depletion of cytokines and a slowing down of proteolytic remodeling. This, in turn, can lead to the development of muscular abnormalities, including dysfunction, weakness, and muscle degeneration.

The Differences on the Fatty Infiltration of Paraspinal Muscles between Single- and Multiple-level Intervertebral Disc Degeneration in Patients with Lumbar Disc Herniation.

Multiple-level Intervertebral disc degeneration (IDD) in patients with lumbar disc herniation (LDH) is related to postoperative re-herniation and low back pain. Although many investigators believed that there is an interdependence between paraspinal muscles degeneration and IDD, few studies focused on the fatty infiltration of paraspinal muscles on single- and multiple-level IDD in patients with LDH. This study aims to investigate the difference on the fatty infiltration of paraspinal muscles between single- and multiple-levels IDD in patients with LDH. and to explore in patients with LDH whether fatty infiltration is a potential risk factor for multiple-level IDD. This study was conducted as a retrospective observational analysis of 82 patients with LDH from January 1, 2020 to December 30, 2020 in our hospital were enrolled. Twenty-seven cases had single-level IDD (Group A), and 55 cases had multiple-level IDD (Group B). We measured the mean computed tomography (CT) density value of the paraspinal muscles, including multifidus (MF), erector spinae (ES) and psoas muscle (PM) at each disc from L1 to S1. Subgroups were set to further analyze the odds ratio (OR) of fatty infiltration of paraspinal muscles in different sex and BMI groups. We measured sagittal angles and analyzed the relationships between these angles and IDD. Finally, we use logistic regression, adjusted for other confounding factors, to investigate whether fatty infiltration is an independent risk factor for multi-level IDD. The average age in multi-level IDD (51.40 ± 15.47 years)was significantly higher than single-level IDD (33.37 ± 7.10 years). The mean CT density value of MF, ES and PM in single-level IDD was significantly higher than multi-level IDD (all ps < 0.001). There was no significant difference of the mean value of angles between the two groups. No matter being fat (body mass index [BMI] > 24.0 kg/m2) or normal, patients with low mean muscle CT density value of MF and ES are significantly easier to suffer from multiple-level IDD. In the pure model, the average CT density value of the MF, ES and PM is all significantly associated with the occurrence of multi-IDD. However, after adjusting for various confounding factors, only the OR of the average CT density value for MF and ES remains statistically significant (OR = 0.810, 0.834, respectively). In patients with LDH, patients with multiple-level IDD have more severe fatty infiltration of MF and ES than those with single-level IDD. Fatty infiltration of MF and ES are independent risk factors for multiple-level IDD in LDH patients.

Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins.

Muscular dystrophies (MDs) are a heterogeneous group of diseases of genetic origin characterized by progressive skeletal muscle degeneration and weakness. There are several types of MDs, varying in terms of age of onset, severity, and pattern of the affected muscles. However, all of them worsen over time, and many patients will eventually lose their ability to walk. In addition to skeletal muscle effects, patients with MDs may present cardiac and respiratory disorders, generating complications that could lead to death. Interdisciplinary management is required to improve the surveillance and quality of life of patients with an MD. At present, pharmacological therapy is only available for Duchene muscular dystrophy (DMD)-the most common type of MD-and is mainly based on the use of corticosteroids. Other MDs caused by alterations in dystrophin-associated proteins (DAPs) are less frequent but represent an important group within these diseases. Pharmacological alternatives with clinical potential in patients with MDs and other proteins associated with dystrophin have been scarcely explored. This review focuses on drugs and molecules that have shown beneficial effects, mainly in experimental models involving alterations in DAPs. The mechanisms associated with the effects leading to promising results regarding the recovery or maintenance of muscle strength and reduction in fibrosis in the less-common MDs (i.e., with respect to DMD) are explored, and other therapeutic targets that could contribute to maintaining the homeostasis of muscle fibers, involving different pathways, such as calcium regulation, hypertrophy, and maintenance of satellite cell function, are also examined. It is possible that some of the drugs explored here could be used to affordably improve the muscular function of patients until a definitive treatment for MDs is developed.

Anabolic Strategies for ICU-Acquired Weakness. What Can We Learn from Bodybuilders?

The study aimed to show the potential clinical application of supplements used among sportsmen for patients suffering from Intensive Care Unit-acquired Weakness (ICUAW) treatment. ICUAW is a common complication affecting approximately 40% of critically ill patients, often leading to long-term functional disability. ICUAW comprises critical illness polyneuropathy, critical illness myopathy, or a combination of both, such as critical illness polyneuromyopathy. Muscle degeneration begins shortly after the initiation of mechanical ventilation and persists post-ICU discharge until proteolysis and autophagy processes normalize. Several factors, including prolonged bedrest and muscle electrical silencing, contribute to muscle weakness, resulting from an imbalance between protein degradation and synthesis. ICUAW is associated with tissue hypoxia, oxidative stress, insulin resistance, reduced glucose uptake, lower adenosine triphosphate (ATP) formation, mitochondrial dysfunction, and increased free-radical production. Several well-studied dietary supplements and pharmaceuticals commonly used by athletes are proven to prevent the aforementioned mechanisms or aid in muscle building, regeneration, and maintenance. While there is no standardized treatment to prevent the occurrence of ICUAW, nutritional interventions have demonstrated the potential for its mitigation. The use of ergogenic substances, popular among muscle-building sociates, may offer potential benefits in preventing muscle loss and aiding recovery based on their work mechanisms.

Advances in the interaction between lumbar intervertebral disc degeneration and fat infiltration of paraspinal muscles: critical summarization, classification, and perspectives.

More than 619 million people in the world suffer from low back pain (LBP). As two potential inducers of LBP, intervertebral disc degeneration (IVDD) and fat infiltration of paraspinal muscles (PSMs) have attracted extensive attention in recent years. So far, only one review has been presented to summarize their relationship and relevant mechanisms. Nevertheless, it has several noticeable drawbacks, such as incomplete categorization and discussion, lack of practical proposals, etc. Consequently, this paper aims to systematically summarize and classify the interaction between IVDD and fat infiltration of PSMs, thus providing a one-stop search handbook for future studies. As a result, four mechanisms of IVDD leading to fat infiltration of PSMs and three mechanisms of fat infiltration in PSMs causing IVDD are thoroughly analyzed and summarized. The typical reseaches are tabulated and evaluated from four aspects, i.e., methods, conclusions, benefits, and drawbacks. We find that IVDD and fat infiltration of PSMs is a vicious cycle that can promote the occurrence and development of each other, ultimately leading to LBP and disability. Finally, eight perspectives are proposed for future in-depth research.

Hysterectomy—a possible risk factor for operative intervention in female patients for degenerative lumbar spine conditions: a case control and cohort study

Researchers have recently linked hysterectomy, which alters sex hormone levels, to diseases like osteoporosis, lumbar spondylolisthesis, hypertension and diabetes etc. However, the association between hysterectomy and lumbar disc herniation (LDH)/lumbar spinal stenosis (LSS) remains unclarified. To determine whether there is a correlation between hysterectomy and surgical intervention for LDH/LSS in women, further substantiated through imaging and clinical research. A case control and cohort study. The study group comprised 1202 female patients aged 45 and older who had undergone operative treatment due to LDH/LSS (825 for LDH and 377 for LSS), and the comparison group comprised 1168 females without lumbar diseases who visited health examination clinic during the same period. One hundred and 2 hysterectomized patients were further selected (Hysterectomy cohort) and matched approximately with the control cohort at a 1:2 ratio from the study group with a minimum follow-up of 2 years. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were calculated to assess the association between hysterectomy and surgical intervention for LDH/LSS in women after adjusted by confounding factors. Patients from both the hysterectomy and control cohorts underwent a comprehensive assessment. This assessment included the evaluation of several parameters: the functional cross-sectional area, fat infiltration rate, relative functional cross-sectional area of the lumbar paravertebral muscles, facet joint degeneration grade, cartilage endplate damage, Modic changes for the L3/4-L5/S1 segments, Pfirrmann grade of lumbar disc degeneration, and disc height index for the L1/2-L5/S1 segments. Additionally, the Visual Analog Scale (VAS) and Japanese Orthopaedic Association (JOA) scores were recorded preoperatively and at the last follow-up. Associations between hysterectomy and patients treated surgically for LDH or LSS were analyzed using multivariate binomial logistic regression analysis. Lumbar X-ray, computed tomography (CT) and magnetic resonance imaging (MRI) were used to evaluate the imaging variables. Imaging and clinical variables were compared. Hysterectomized women were associated with requiring surgery due to LDH/LSS, with ORs of 2.613 (p<.001) and 2.084 (p=.006), respectively. The imaging evaluation further revealed that the hysterectomy cohort had more severe degeneration of the paraspinal muscles, facet joints, endplates, and intervertebral discs, Modic changes at L3/4-L5/S1 segments, and intervertebral height reduction at L1/2-L5/S1 segments when compared to the control cohort (p<.01). Compared to the control cohort, the hysterectomy cohort exhibited higher preoperative and last follow-up VAS scores for low back pain, and last follow-up JOA scores (p<.01). Based on the findings of this study, it seems that women who have had a hysterectomy are correlated with requiring surgical intervention due to LDH/LSS. Imaging and clinical studies also indicate that hysterectomized patients exhibited more severe lumbar degeneration and back pain.

Correlation between degeneration of cervical intervertebral disc and degeneration of paravertebral muscle.

To investigate the relationship between degeneration of cervical intervertebral disc and degeneration of paravertebral muscles[multifidus (MF), cervical semispinalis (SCer), semispinalis capitis (SCap) and splenius capitis (SPL)]. 82 patients with chronic neck pain were randomly selected, including 43 males and 39 females, with 50.73 0.7.51 years old. All patients were scanned by 3.0T MRI Philips Ingenia performed conventional MRI sequence scanning and fat measurement sequence mDIXON-Quant scanning of cervical. Fat infiltration (FI) and cross-sectional area (CSA) of cervical paravertebral muscle (MF, SCer, SCap and SPL) at central level of C5-6 disc were measured by Philips 3.0T MRI image post-processing workstation. According to Pfirrmann grading system, there was no grade I in the included cases. The number of grade IIr IV cases were n=16, 40, 19 and 7 respectively. CSA and FI of cervical paravertebral muscles were compared with t test or one-way ANOVA, Spearman correlation analysis was used to evaluate the correlation between age, disc degeneration, and CSA, FI of cervical paravertebral muscles, and multiple linear regression analysis was used to analyze the independent influencing factors of CSA and FI. CSA of cervical paravertebral muscles in male patients was significantly higher than that in female patients (all P<0.001), but there was no significant difference in FI (all P>0.05). Age was weakly correlated with CSA of MF+SCer, moderately correlated with CSA of SCap and SPL (r=-0.256, -0.355 and -0.361, P<0.05), weakly correlated with FI of SCap and SPL (r= 0.182 and 0.264, P<0.001), moderately correlated with FI of MF+SCer (r=0.408, P<0.001). There were significant differences in FI with disc degeneration (P<0.001, P=0.028 and P=0.005). Further correlation analysis showed that disc degeneration was strongly correlated with FI of MF+SCer (r=0.629, P<0.001), and moderately correlated with FI of SCap and SPL (r=0.363, P=0.001; r=0.345, P=0.002). Multiple linear regression analysis showed that sex and age were the influencing factors of CSA of SCap and SPL, sex was the independent influencing factor of CSA of MF+SCer, and disc degeneration was the independent influencing factor of FI. Age is negatively correlated with CSA and positively correlated with FI. Disc degeneration was correlated with FI of paravertebral muscles, especially with FI of MF and SCer. Sex and age were the influencing factors of CSA, while disc degeneration was the independent influencing factor of FI.

Short-term treatment with Uncaria tomentosa aggravates the injury phenotype in mdx mice

Introduction: Uncaria tomentosa (Willd. ex Roem. &amp; Schult.) DC. (Rubiaceae) or UT is a medicinal plant with antiviral, antimutagenic, anti-inflammatory and antioxidant properties. Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by mutations in the dystrophin gene; this deficiency leads to sarcolemma instability, inflammation, muscle degeneration and fibrosis. Objective: Considering the importance of inflammation to dystrophy progression and the anti-inflammatory activity of UT, in the present study we evaluated whether oral administration of UT extract would ameliorate dystrophy in the mdx mice, a DMD model. Methods: Eight-week-old male mdx mice were submitted to 200 mg/kg body weight daily UT oral administration for 6 weeks. General histopathology was analysed, and muscle tumor necrosis factor α, transforming growth factor-β, myostatin and osteopontin transcript levels were assessed. The ability of mice to sustain limb tension to oppose their gravitational force was measured. Data were analysed with the unpaired Student’s t-test. Results: Morphologically, both untreated and UT-treated animals exhibited internalised nuclei, increased endomysial connective tissue and variations in muscle fibre diameters. Body weight and muscle strength were significantly reduced in the UT-treated animals. Blood creatine kinase was higher in UT-treated compared to untreated animals. In tibialis anterior, myostatin, transcript was more highly expressed in the UT-treated while in the diaphragm muscle, transforming growth factor-β transcripts were less expressed in the UT-treated. Conclusion: While previous studies identified anti-inflammatory, antiproliferative and anticarcinogenic UT effects, the extract indicates worsening of dystrophic muscles phenotype after short-term treatment in mdx mice.

Follistatin-respiratory connection predicting all-cause mortality among community-dwelling middle-to-old age individuals: Results from the I-Lan Longitudinal Study

ObjectivesThe link between aging and pulmonary function decline is well-established, but the underlying mechanisms have yet to be fully revealed. Serum follistatin, a myokine implicated in muscle degeneration, may play a role in age-related pulmonary changes. This study aims to investigate the relationship between serum follistatin levels and pulmonary function decline in community-dwelling older adults, and evaluate their combined association with all-cause mortality. Research design and methodsThis longitudinal cohort study utilized data from 751 participants aged ≥50 years in the I-Lan Longitudinal Aging Study between 2018−2019. Serum follistatin levels, spirometry results, demographic and clinical data were retrieved. Participants were stratified based on their follistatin levels. Survival curves and group comparisons based on follistatin levels and decline in peak expiratory flow (PEF) using Kaplan-Meier analysis and log-rank tests. Multivariate Cox proportional hazards models were further used to identify independent predictors of all-cause mortality during the 52-month follow-up. ResultsElevated follistatin levels significantly correlated with worse pulmonary function, particularly decreased PEF (p = 0.030). Kaplan–Meier analysis revealed the combination of elevated follistatin levels and decreased PEF was associated with increased risk of all-cause mortality (Log-rank p = 0.023). Cox proportional hazards models further identified that concurrent presence of higher follistatin levels and decreased PEF predicted higher risk of all-cause mortality (adjusted HR 3.58, 95% CI: 1.22–10.53, p = 0.020). ConclusionHigher serum follistatin levels correlate with decreased pulmonary function, specifically PEF decline, in community-dwelling older adults. Furthermore, the coexistence of elevated follistatin levels and decreased PEF was associated with risk of all-cause mortality. Follistatin may serve as a biomarker for pulmonary aging and related adverse outcomes.

Paraspinal muscle endurance and morphology (PMEM) score: a new method for prediction of postoperative mechanical complications after lumbar fusion

BACKGROUND CONTEXTAlthough the relationships between paraspinal muscles and lumbar degenerative disorders have been acknowledged, paraspinal muscle evaluation has not been incorporated into clinical therapies. PURPOSEWe aimed to establish a novel paraspinal muscle endurance and morphology (PMEM) score to better predict mechanical complications after lumbar fusion. STUDY DESIGNProspective cohort study. PATIENT SAMPLEA total of 212 patients undergoing posterior lumbar interbody fusion with at least 1 year of follow-up were finally included. OUTCOME MEASURESMechanical complications including screw loosening, pseudarthrosis and other complications like cage subsidence, and patient-reported outcomes were evaluated at last follow-up. METHODSThe PMEM score comprised 1 functional muscular parameter (the performance time of the endurance test) and 2 imaging muscular parameters (relative functional cross-sectional area [rFCSA] of paraspinal extensor muscles [PEM] and psoas major [PS] on magnetic resonance imaging). The score was established based on a weighted scoring system created by rounding β regression coefficients to the nearest integer in univariate logistic regression. The diagnostic performance of the PMEM score was determined by binary logistic regression model and receiver operating characteristic (ROC) curve with the area under the curve (AUC). Additionally, pairwise comparisons of ROC curves were conducted to compare the diagnostic performance of the PMEM score with conventional methods based on a single muscular parameter. Moreover, differences of mechanical complications and patient-reported outcomes among the PMEM categories were analyzed using Chi-square test with Bonferroni correction. RESULTSThe PMEM score, calculated by adding the scores for each parameter, ranges from 0 to 5 points. Patients with higher PMEM scores exhibited higher rates of mechanical complications (p<.001). Binary logistic regression revealed that the PMEM score was an independent factor of mechanical complications (p<.001, OR=2.002). Moreover, the AUC of the PMEM score (AUC=0.756) was significantly greater than those of the conventional methods including the endurance test (AUC=0.691, Z=2.036, p<.05), PEM rFCSA (AUC=.690, Z=2.016, p<.05) and PS rFCSA (AUC=0.640, Z=2.771, p<.01). In terms of the PMEM categories, a score of 0–1 was categorized as low-risk muscular state of mechanical complications; 2–3, as moderate; and 4–5, as high-risk state. Moving from the low-risk state to the high-risk state, there was a progressive increase in the rates of mechanical complications (13.8% vs 32.1% vs 72.7%; p<.001), and a decrease in the rates of clinically significant improvement of patient-reported outcomes (all p<.05). CONCLUSIONSThe PMEM score might comprehensively evaluate paraspinal muscle degeneration and exhibit greater ability in predicting mechanical complications than the conventional evaluations after lumbar fusion. Surgeons might develop individualized treatment strategy tailored to different muscle degeneration statuses reflected by the PMEM score for decreasing the risk of mechanical complications.

The Drosophila Nesprin-1 homolog MSP300 is required for muscle autophagy and proteostasis.

Nesprin proteins, which are components of the linker of nucleoskeleton and cytoskeleton (LINC) complex, are located within the nuclear envelope and play prominent roles in nuclear architecture. For example, LINC complex proteins interact with both chromatin and the cytoskeleton. Here, we report that the Drosophila Nesprin MSP300 has an additional function in autophagy within larval body wall muscles. RNAi-mediated MSP300 knockdown in larval body wall muscles resulted in defects in the contractile apparatus, muscle degeneration and defective autophagy. In particular, MSP300 knockdown caused accumulation of cytoplasmic aggregates that contained poly-ubiquitylated cargo, as well as the autophagy receptor ref(2)P (the fly homolog of p62 or SQSTM) and Atg8a. Furthermore, MSP300 knockdown larvae expressing an mCherry-GFP-tagged Atg8a transgene exhibited aberrant persistence of the GFP signal within these aggregates, indicating failure of autophagosome maturation. These autophagy deficits were similar to those exhibited by loss of the endoplasmic reticulum (ER) fusion protein Atlastin (Atl), raising the possibility that Atl and MSP300 might function in the same pathway. In support of this possibility, we found that a GFP-tagged MSP300 protein trap exhibited extensive localization to the ER. Alteration of ER-directed MSP300 might abrogate important cytoskeletal contacts necessary for autophagosome completion.

The Role of MicroRNA in the Pathogenesis of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked progressive disorder associated with muscle wasting and degeneration. The disease is caused by mutations in the gene that encodes dystrophin, a protein that links the cytoskeleton with cell membrane proteins. The current treatment methods aim to relieve the symptoms of the disease or partially rescue muscle functionality. However, they are insufficient to suppress disease progression. In recent years, studies have uncovered an important role for non-coding RNAs (ncRNAs) in regulating the progression of numerous diseases. ncRNAs, such as micro-RNAs (miRNAs), bind to their target messenger RNAs (mRNAs) to suppress translation. Understanding the mechanisms involving dysregulated miRNAs can improve diagnosis and suggest novel treatment methods for patients with DMD. This review presents the available evidence on the role of altered expression of miRNAs in the pathogenesis of DMD. We discuss the involvement of these molecules in the processes associated with muscle physiology and DMD-associated cardiomyopathy.

Effects of a Ketogenic Diet on the Assessment of Biochemical and Clinical Parameters in Duchenne Muscular Dystrophy: A Preclinical Investigation.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive skeletal muscle degeneration and systemic effects, including the central nervous system (CNS). This study aimed to assess the impact of a 14-day ketogenic diet (DCet) on biochemical and clinical parameters in a DMD mouse model. Young adult mice (50 days old) were fed DCet, while control groups received a standard diet. On the 14th day, memory and behavior tests were conducted, followed by biochemical evaluations of oxidative stress, inflammatory biomarkers, body weight, feed intake, and brain-derived neurotrophic factor (BDNF) levels. mdx + DCet mice showed reduced mass (0.2 g ± 2.49) and improved memory retention (p < 0.05) compared to controls. Oxidative damage in muscle tissue and CNS decreased, along with a significant cytokine level reduction (p <0.05). The protocol led to an increase in hippocampal BDNF and mitochondrial respiratory complex activity in muscle tissue and the central nervous system (CNS), while also decreasing creatine kinase activity only in the striatum. Overall, a 14-day DCet showed protective effects by improving spatial learning and memory through reductions in oxidative stress and immune response, as well as increases in BDNF levels, consistent with our study's findings.

Adverse plasma branched-chain amino acid profile mirrors fatty muscle degeneration in diabetic heart failure patients.

Elevated plasma branched-chain amino acids (BCAAs) are tightly linked to incident diabetes and its complications, while lower BCAAs are associated with adverse outcomes in the elderly and heart failure (HF) patients. The interplay between body compositions and plasma BCAAs, especially under the influence of co-morbid diabetes in HF patients, is not well understood. Here, we examined the impact of diabetes on the prognostic value of plasma BCAA and its association with body compositions in HF patients. We retrospectively examined 301 HF patients (70±15years old; 59% male), among which 36% had diabetes. Blood samples for plasma BCAA measurements were collected in a fasting state after stabilization of HF and analysed using ultraperformance liquid chromatography. A dual-energy X-ray absorptiometry scan assessed regional body compositions, and muscle wasting was defined as appendicular skeletal muscle mass index (ASMI)<7.00 and <5.40kg/m2 for males and females, respectively, according to the criteria of the Asian Working Group for Sarcopenia. Although analyses of covariance revealed that plasma BCAAs were significantly higher in diabetic patients, low valine (<222.1nmol/mL) similarly predicted adverse events defined by HF hospitalization, lethal arrhythmia, or all-cause death in both diabetic and non-diabetic patients independently of age, sex, and NT-proBNP (adjusted hazard ratio [HR] 3.1, 95% confidence interval [CI] of 1.1-8.6 and adjusted HR 2.67, 95% CI 1.1-6.5, respectively; P for interaction 0.88). In multivariate linear regression analyses comprising age, sex, and regional body compositions as explanatory variables, plasma BCAAs were positively correlated with visceral adipose tissue area in non-diabetic patients (standardized β coefficients [β]=0.44, P<0.001). In contrast, in diabetic patients, plasma BCAAs were correlated positively with ASMI (β=0.49, P=0.001) and negatively with appendicular fat mass index (AFMI; β=-0.42, P=0.004). Co-morbid diabetes was independently associated with muscle wasting (adjusted odds ratio 2.1, 95% CI 1.1-4.0) and significantly higher plasma 3-methylhistidine level, a marker of myofibrillar degradation. In diabetic patients, ASMI uniquely showed a J-shaped relationship with AFMI, and in a subgroup of HF patients with muscle wasting, diabetic patients showed 12% higher AFMI than non-diabetic patients despite comparable ASMI reductions. Despite higher plasma BCAA levels in HF patients with diabetes, the prognostic value of low valine remained consistent regardless of diabetes status. However, low BCAAs were distinctly associated with fatty muscle degeneration in the extremities in diabetic patients, suggesting the importance of targeted interventions to prevent such tissue remodelling in this population.

CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance

Mitochondria play a central role in muscle metabolism and function. A unique family of iron-sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3-NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.