Severe Muscle Atrophy Research Articles

The Suprascapular Artery as a Reference for the Evaluation of Supraspinatus Fatty Infiltration on Magnetic Resonance Imaging.

Fatty infiltration (FI) of the supraspinatus is commonly seen in chronic large-to-massive rotator cuff tears. Evaluating FI in patients with severe muscle atrophy can be confusing. The purpose of this study was to investigate the anatomic relationship between the suprascapular artery and supraspinatus muscle on magnetic resonance imaging (MRI) to provide a method for defining the border of the supraspinatus muscle on Y-view MRI. It was hypothesized that the branches of the suprascapular artery would encircle the supraspinatus muscle on Y-view and adjacent MRI slices and could be used for defining the supraspinatus outline on oblique sagittal images. Cohort study (diagnosis); Level of evidence, 3. A total of 172 shoulders that had undergone arthroscopic repair for large-to-massive rotator cuff tears were retrospectively included. Two methods, one based on the supraspinous fossa and trapezius (SF method) and the other based on the region bounded by the branches of the suprascapular artery (SA method), were used for defining the supraspinatus outline on Y-view MRI for the assessment of FI. Preoperative supraspinatus FI grade and tangent sign and postoperative tendon integrity were evaluated. Shoulder function was assessed using the American Shoulder and Elbow Surgeons (ASES) score and active range of motion. The branches of the suprascapular artery encircled the supraspinatus in all shoulders, with the diameter of the branches ranging from 0.5 to 3 mm. The agreement in supraspinatus FI grading between the SF and SA methods was 65.12%. When limited to the 61 shoulders with a positive tangent sign, the agreement dropped to 22.95% (κ = 0.032). The group (FI grade 2 by SA method and ≥3 by SF method) showed no significant difference in postoperative outcomes compared with the 2-vs-2 group but had significantly better postoperative ASES scores (P = .001) and active range of motion in forward elevation (P = .020) compared with the ≥3-vs-≥3 group. The tangent sign was positive in 92.16% of the 2-vs-≥3 group. The suprascapular artery is a reliable reference for the evaluation of supraspinatus FI. When a positive tangent sign presents, supraspinatus FI is likely to be overestimated if the hyperintensity outside the region bounded by the branches of the suprascapular artery is mistaken as FI.

Which muscle is the external rotation compensator after superior capsular reconstruction?

BackgroundSuperior capsular reconstruction (SCR) is a surgical option for massive irreparable rotator cuff tears, particularly involving the supraspinatus and infraspinatus. In this procedure, the torn infraspinatus is not repaired or reconstructed. However, an improvement in postoperative external rotation (ER) angle and strength is observed. There is a lack of studies explaining how ER is restored after SCR. The aim of this study is to identify the ER compensator by assessing the muscle volume of the posterior deltoid and teres minor. MethodsSixty-eight patients with massive rotator cuff tears underwent SCR during 2016-2021. Of these patients, 28 who met the following inclusion criteria were retrospectively reviewed: (1) massive rotator cuff tears including the supraspinatus and infraspinatus; (2) severe muscle atrophy and fatty change; (3) intact or reparable subscapularis tendon; (4) Hamada of grade 3 or lower. Posterior deltoid and teres minor volume were measured by using an open-source medical image processing software preoperatively and 1-year postoperatively. The percentage of the posterior deltoid and teres minor muscle volume change was compared between patients with 1-year postoperative ER manual motor testing (MMT) of grade 5 and of grade < 5. The relationship between grade of fatty change, percentage of the muscle volume change, and ER angle and strength were evaluated. ResultsThere was a significant increase in the 1-year postoperative teres minor volume compared with the preoperative volume (24.6±10.3 cm³ versus 20.9±8.3 cm³, p<0.000), while the posterior deltoid volume remained unchanged (178.1±48.3 cm³ versus 178.8±47 cm³). Patients with ER MMT of grade 5 had a greater teres minor volume compared to those with an ER MMT grade of less than 5 (22.3% versus 9.4%), although this difference was not significant (p=0.074, 95% CI=-1.3–27.0). The posterior deltoid volume showed no significant change. The percentage of teres minor volume change had a weak positive correlation with ER strength (r=0.308, p=0.055, 95% CI=-0.02–1.0). There was a significant negative correlation between ER strength and the severity of both preoperative and postoperative fatty changes in the teres minor (r=-0.258, p=0.065, 95% CI=-1.0–-0.042 and r=-0.323, p=0.028, 95% CI=-1.0–-0.113, respectively). The pre- and postoperative fatty changes in the teres minor were negatively correlated with the percentage of teres minor volume change (r=-0.298, p=0.062, 95% CI=-1.0–0.031 and r=-0.413, p=0.015, 95% CI=-1.0–-0.1, respectively). ConclusionThe teres minor may serve as a potential compensator for ER in patients with massive rotator cuff tears following SCR.

AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice

BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS.MethodsWe used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice.ResultsSOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice.ConclusionsAAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.

Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin-desmin double knockout (DKO) mouse.

Limited knowledge exists regarding the chronic effect of muscular exercise on muscle function in a murine model of severe Duchenne muscular dystrophy (DMD). Here we determined the effects of 1month of voluntary wheel running (WR), 1month of enforced treadmill running (TR) and 1month of mechanical overloading resulting from the removal of the synergic muscles (OVL) in mice lacking both dystrophin and desmin (DKO). Additionally, we examined the effect of activin receptor administration (AR). DKO mice, displaying severe muscle weakness, atrophy and greater susceptibility to contraction-induced functional loss, were exercised or treated with AR at 1month of age and in situ force production of lower leg muscle was measured at the age of 2months. We found that TR and OVL increased absolute maximal force and the rate of force development of the plantaris muscle in DKO mice. In contrast, those of the tibialis anterior (TA) muscle remained unaffected by TR and WR. Furthermore, the effects of TR and OVL on plantaris muscle function in DKO mice closely resembled those in mdx mice, a less severe murine DMD model. AR also improved absolute maximal force and the rate of force development of the TA muscle in DKO mice. In conclusion, exercise training improved plantaris muscle weakness in severely affected dystrophic mice. Consequently, these preclinical results may contribute to fostering further investigations aimed at assessing the potential benefits of exercise for DMD patients, particularly resistance training involving a low number of intense muscle contractions. KEY POINTS: Very little is known about the effects of exercise training in a murine model of severe Duchenne muscular dystrophy (DMD). One reason is that it is feared that chronic muscular exercise, particularly that involving intense muscle contractions, could exacerbate the disease. In DKO mice lacking both dystrophin and desmin, characterized by severe lower leg muscle weakness, atrophy and fragility in comparison to the less severe DMD mdx model, we found that enforced treadmill running improved absolute maximal force of the plantaris muscle, while that of tibialis anterior muscle remained unaffected by both enforced treadmill and voluntary wheel running. Furthermore, mechanical overloading, a non-physiological model of chronic resistance exercise, reversed plantaris muscle weakness. Consequently, our findings may have the potential to alleviate concerns and pave the way for exploring the prescription of endurance and resistance training as a viable therapeutic approach for the treatment of dystrophic patients. Additionally, such interventions may serve in mitigating the pathophysiological mechanisms induced by physical inactivity.

French National Protocol for diagnosis and care of facioscapulohumeral muscular dystrophy (FSHD).

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common genetically inherited myopathies in adults. It is characterized by incomplete penetrance and variable expressivity. Typically, FSHD patients display asymmetric weakness of facial, scapular, and humeral muscles that may progress to other muscle groups, particularly the abdominal and lower limb muscles. Early-onset patients display more severe muscle weakness and atrophy, resulting in a higher frequency of associated skeletal abnormalities. In these patients, multisystem involvement, including respiratory, ocular, and auditory, is more frequent and severe and may include the central nervous system. Adult-onset FSHD patients may also display some degree of multisystem involvement which mainly remains subclinical. In 95% of cases, FSHD patients carry a pathogenic contraction of the D4Z4 repeat units (RUs) in the subtelomeric region of chromosome 4 (4q35), which leads to the expression of DUX4 retrogene, toxic for muscles (FSHD1). Five percent of patients display the same clinical phenotype in association with a mutation in the SMCHD1 gene located in chromosome 18, inducing epigenetic modifications of the 4q D4Z4 repeated region and expression of DUX4 retrogene. This review highlights the complexities and challenges of diagnosing and managing FSHD, underscoring the importance of standardized approaches for optimal patient outcomes. It emphasizes the critical role of multidisciplinary care in addressing the diverse manifestations of FSHD across different age groups, from skeletal abnormalities in early-onset cases to the often-subclinical multisystem involvement in adults. With no current cure, the focus on alleviating symptoms and slowing disease progression through coordinated care is paramount.

Development of an Exercise-based EV Therapy to Improve Skeletal Muscle Recovery After Immobilization

Introduction: Immobilization is necessary for recovery from illness or bone fractures; however, prolonged immobilization can result in significant loss of muscle mass and function. It is critical to recover muscle mass quickly following immobilization as severe muscle atrophy is correlated with increased likelihood of metabolic disorders, disability, and mortality. Physical rehabilitation can improve outcomes but is not always feasible. The purpose is to determine the extent to which EVs circulating in blood after endurance exercise training (EnVs) act as a safe and effective therapy to recover skeletal muscle mass following disuse. Methods: Donor C57BL/6 mice (n = 8-10, 4-month-old) were provided access to horizontal running wheels in a locked (sedentary) or unlocked (exercise) condition. After 4 weeks of voluntary running, EVs (SedVs or EnVs) were isolated from plasma using size exclusion chromatography according to manufactures guidelines, and concentration confirmed via nanoparticle tracking analysis (NanoSight NS3000). Recipient C57BL6/J mice (n = 5-8, 4-month-old) were subjected to single limb immobilization for 14 days. Upon remobilization, mice received a single intramuscular injection of PBS, SedVs, EnVs, or endurance plasma proteins, and remobilized for 3 and 14 days. Muscle samples were collected after remobilization and assessed for muscle cross-sectional-area (CSA) and capillarization. Results: Upon 3-day remobilization, EnVs did not significantly recover global fiber CSA and fiber-type specific CSA (Type IIa, Type IIx or Type IIb) or capillarization. Upon 14-day remobilization, EnVs did not significantly improve global fiber CSA and fiber-type specific CSA. However, a significant treatment effect was observed for capillary density (P = 0.0445), with increases observed for both SedV (P = 0.034) and EnV (P = 0.0117). Conclusion: EVs isolated from plasma after exercise can significantly improve skeletal muscle vascularization after immobilization, which may represent an important step toward full recovery of skeletal muscle mass. Partially support by NIH (NIAMS R01AR072735). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Interleukin-1β triggers muscle-derived extracellular superoxide dismutase expression and protects muscles from doxorubicin-induced atrophy

Oxidative stress plays an important role in skeletal muscle atrophy. Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Since doxorubicin-induced muscle atrophy is primarily attributable to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. This study aimed at demonstrating that doxorubicin triggered severe muscle atrophy via upregulation of oxidative stress (4-Hydroxynonenal and Malondialdehyde) and atrogenes (Atrogin-1/MAFbx and Muscle RING Finger-1) in association with decreased expression of the antioxidant enzyme, extracellular superoxide dismutase (EcSOD), in cultured C2C12 myotubes and mouse skeletal muscle. EcSOD recombinant protein supplementation elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1β (IL-1β) mRNA expression in cultured myotubes and skeletal muscle, while transient IL-1β treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1β treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which is associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1β signaling is a potential therapeutic approach against doxorubicin-and oxidative stress-mediated muscle atrophy. This study was supported by Grant-in-Aid for Scientific Research (B) (15H03080, 18H03153, 21H03326), Grant-in-Aid for Exploratory Research (20K21766), Suzuken Memorial Foundation, Toyoaki Scholarship Foundation, The Nakatomi Foundation, and The Uehara Memorial Foundation (to M.O.). This research was also supported by Grant-in-Aid for JSPS Fellows (20J15551), Grant-in-Aid for Early-Career Scientists (22K17733), Suzuken Memorial Foundation, The Nakatomi Foundation, and The Uehara Memorial Foundation (to M.Y.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital contractural syndrome 3

BackgroundBiallelic pathogenic variants in PIP5K1C (MIM #606,102) lead to lethal congenital contractural syndrome 3 (LCCS3, MIM #611,369), a rare autosomal recessive genetic disorder characterized by small gestational age, severe multiple joint contractures and muscle atrophy, early death due to respiratory failure. Currently, 5 individuals with LCCS3 were reported and 5 pathogenic variants in PIP5K1C were identified. Here, we reported the two fetuses in a Chinese pedigree who displayed multiple joint contractures and other congenital anomalies.MethodsTrio-based whole-exome sequencing (WES) was performed for the parents and the recent fetus to detect the genetic cause for fetus phenotype.ResultsA novel variant, NM_012398.3: c.949_952dup, p.S318Ifs*28 and a previously reported variant, c.688_689del, p.G230Qfs*114 (ClinVar database) in PIP5K1C, were detected in the individuals, and these variants were inherited from the mother and father, respectively. We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers, which have not been delineated detailedly in previously reported LCCS3 individuals. Furthermore, novel phenotype, bilateral dilated lateral ventricles, was revealed in one fetus.ConclusionsThese findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3, which will help with the prenatal diagnosis and genetic counseling for this family.

A chronic form of tick-borne encephalitis. Case report

Background: Chronic tick-borne encephalitis is a rare and not fully understood pathology in which the body is not able to completely get rid of the virus. The virus remains in the nervous system mainly in the motor structures, supporting the degenerative-inflammatory process in them. Clinical case description: A clinical case of a chronic form of tick-borne encephalitis, steadily progressing, in a young man with a completely intact cognitive sphere is described. Damage to the motor nuclei of the trunk, motoneurons of the anterior horns of the spinal cord led to gross bulbar disorders, severe diffuse muscle atrophy with difficulty in independent movement. Conclusion: The above observation of the amyotrophic form of tick-borne encephalitis reflects the remitting-progressive nature of the course for 1.5 years.

Minimally invasive removal of dumbbell shaped schwannomas with transforaminal lumbar fusion: a retrospective study with a minimum 3-year follow-up

To evaluate the effectiveness and long-term results of minimally invasive resection of dumbbell-shaped lumbar schwannomas Eden type 2 and 3 combined with transforaminal lumbar interbody fusion and transpedicular stabilization. A retrospective study included 13 patients (8 men and 5 women) with lumbar dumbbell tumors Eden type 2 and 3 who underwent minimally invasive facetectomy through posterolateral anatomical corridor, microsurgical tumor resection and MI TLIF. We analyzed intraoperative parameters, neurological functions (ASIA scale), clinical characteristics (ODI, SF-36), and complications. Resection quality and area of the multifidus muscle were assessed according to MRI data. All patients were followed-up throughout at least 3-year. Surgery time was 147 min, blood loss - 118 ml, hospital-stay - 7 days. Clinical parameters significantly improved in the follow-up period: ODI score decreased from 72 to 12 (p=0.004), SF-36 PCS increased from 26.24 to 48.51 (p=0.006) and MCS score increased from 29.13 to 53.68 (p=0.002). According to MRI data, no tumor recurrences and severe muscle atrophy (>30%) were observed after 3 years in all cases. Superficial wound infection occurred in 1 (7.7%) case. There were normal neurological functions (ASIA type E) in all patients. Minimally invasive facetectomy through posterolateral approach with MI TLIF technology can be used for safe and effective resection of dumbbell-shaped schwannomas Eden type 2 and 3.

Cognitive impairment in children with 5q-associated spinal muscular atrophy type 1: two case reports and the review of the literature.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5, leading to the degeneration of lower motor neurons. There are few studies on cognitive impairment comorbid with SMA. Here, we report two cases of severe cognitive impairment in Chinese children with SMA type 1, marking the first such reports in this demographic. We propose that severe cognitive dysfunction may be a comorbidity of SMA. Clinicians should consider SMA in patients presenting with severe muscle weakness and atrophy accompanied by cognitive impairments, to avoid misdiagnosis and oversight.

Development and Characterization of a Cancer Cachexia Rat Model Transplanted with Cells of the Rat Lung Adenocarcinoma Cell Line Sato Lung Cancer (SLC).

Cancer cachexia is a complex malnutrition syndrome that causes progressive dysfunction. This syndrome is accompanied by protein and energy losses caused by reduced nutrient intake and the development of metabolic disorders. As many as 80% of patients with advanced cancer develop cancer cachexia; however, an effective targeted treatment remains to be developed. In this study, we developed a novel rat model that mimics the human pathology during cancer cachexia to elucidate the mechanism underlying the onset and progression of this syndrome. We subcutaneously transplanted rats with SLC cells, a rat lung adenocarcinoma cell line, and evaluated the rats' pathophysiological characteristics. To ensure that our observations were not attributable to simple starvation, we evaluated the characteristics under tube feeding. We observed that SLC-transplanted rats exhibited severe anorexia, weight loss, muscle atrophy, and weakness. Furthermore, they showed obvious signs of cachexia, such as anemia, inflammation, and low serum albumin. The rats also exhibited weight and muscle losses despite sufficient nutrition delivered by tube feeding. Our novel cancer cachexia rat model is a promising tool to elucidate the pathogenesis of cancer cachexia and to conduct further research on the development of treatments and supportive care for patients with this disease.

Interleukin-1β triggers muscle-derived extracellular superoxide dismutase expression and protects muscles from doxorubicin-induced atrophy.

Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Given that doxorubicin-induced muscle atrophy is attributable primarily to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. The aim of this study was to demonstrate that doxorubicin triggers severe muscle atrophy via upregulation of oxidative stress (4-hydroxynonenal and malondialdehyde) and atrogenes (atrogin-1/MAFbx and muscle RING finger-1) in association with decreased expression of the antioxidant enzyme extracellular superoxide dismutase (EcSOD), in cultured C2C12myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1β (IL-1β) mRNA expression in cultured myotubes and skeletal muscle, whereas transient IL-1β treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1β treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which was associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1β signalling is a potential therapeutic approach to counteract the muscle atrophy mediated by doxorubicin and oxidative stress. KEY POINTS: Doxorubicin, a commonly prescribed chemotherapeutic agent for patients with cancer, induces severe muscle atrophy owing to increased expression of oxidative stress; however, protective therapeutic targets are poorly understood. Doxorubicin induced muscle atrophy owing to increased expression of oxidative stress and atrogenes in association with decreased protein expression of extracellular superoxide dismutase (EcSOD) in cultured C2C12myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein increased EcSOD levels on the cellular membrane of cultured myotubes, resulting in inhibition of doxorubicin-induced oxidative stress and myotube atrophy. Doxorubicin treatment decreased interleukin-1β (IL-1β) expression in cultured myotubes and skeletal muscle, whereas transient IL-1β treatment in vivo and in vitro increased EcSOD protein expression and attenuated doxorubicin-induced muscle atrophy. These findings reveal that regulation of skeletal muscle EcSOD via maintenance of IL-1β signalling is a possible therapeutic approach for muscle atrophy mediated by doxorubicin and oxidative stress.

Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads

Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it’s low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy.

Role of growth differentiation factor 15 in cancer cachexia (Review).

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β family, is a stress-induced cytokine. Under normal circumstances, the expression of GDF15 is low in most tissues. It is highly expressed during tissue injury, inflammation, oxidative stress and cancer. GDF15 has been established as a biomarker in patients with cancer, and is associated with cancer cachexia (CC) and poor survival. CC is a multifactorial metabolic disorder characterized by severe muscle and adipose tissue atrophy, loss of appetite, anemia and bone loss. Cachexia leads to reductions in quality of life and tolerance to anticancer therapy, and results in a poor prognosis in cancer patients. Dysregulated GDF15 levels have been discovered in patients with CC and animal models, where they have been found to be involved in anorexia and weight loss. Although studies have suggested that GDF15 mediates anorexia and weight loss in CC through its neuroreceptor, glial cell-lineage neurotrophic factor family receptor α-like, the effects of GDF15 on CC and the potential regulatory mechanisms require further elucidation. In the present review, the characteristics of GDF15 and its roles and molecular mechanisms in CC are elaborated. The targeting of GDF15 as a potential therapeutic strategy for CC is also discussed.

TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.

When and how much does the muscle strength recover after arthroscopic superior capsular reconstruction?

Recently, arthroscopic superior capsular reconstruction (SCR) has been performed for irreparable large to massive rotator cuff tears and its excellent clinical results have also been reported. Although the muscle strength was reported to recover, it is not clarified yet when and how much it recovers. The purpose of this study was to determine the recovery pattern of muscle strength after SCR. Thirty-five patients (mean age: 65 years) who met the following inclusion criteria were retrospectively reviewed: 1) those with large to massive, irreparable tears of the rotator cuff including the supraspinatus and infraspinatus tendons; 2) those with severe muscle atrophy and fatty change; 3) those with their muscle quality and strength assessed by MRI and a dynamometer at 6 months, 1 year, and 2 years; 4) those with a minimum follow-up of 2 years; and 5) those without severe osteoarthritis. The isometric muscle strength of scaption, internal and external rotation in adduction was measured twice for each motion by a dynamometer. Relative to the muscle strength of the uninvolved side, the involved side showed 61 ± 21% in scaption, 63 ± 20% in external rotation, and 103 ± 29% in internal rotation at 2 years after surgery. Whereas no significant differences were observed between 1-year and 2-year follow-ups, there was a significant difference in muscle strength of scaption between 6-months and 1-year (P = 0.0174). Graft retear was seen in 5 cases (14%). There was a trend that the muscle strength of scaption and external rotation in the no retear group was greater than that in the retear group despite no significant difference (P = 0.0717, P = 0.0824, respectively). The recovery of the muscle strength after SCR was observed until 1 year after surgery and the muscle strength of scaption and external rotation returned to 60% of the uninvolved side at 2 years.

Amyotrophic lateral sclerosis with respiratory failure and dysautonomia: a case report.

A 58-year-old male presented with left lower limb limping, difficulty climbing stairs, and left foot weakness, followed by right upper limb weakness and was diagnosed with ALS and received edaravone and riluzole treatment. He presented again with right lower limb weakness, shortness of breath, and wide fluctuations in blood pressure, leading to ICU admission with new diagnosis of ALS with dysautonomia with respiratory failure and was managed with non-invasive ventilation, physiotherapy, and gait training exercises. ALS is a progressive neurodegenerative disease affecting motor neurons but non-motor symptoms can also occur, including dysautonomia, which can result in blood pressure fluctuations. Dysautonomia in ALS is caused by several mechanisms such as severe muscle atrophy, prolonged ventilatory support, and upper and lower motor neuron lesions. Management of ALS involves giving a definitive diagnosis, providing nutritional support, using disease-modifying drugs such as riluzole and non-invasive ventilation to improve survival and quality of life. Early diagnosis is essential for effective management of the disease. Early diagnosis, use of disease-modifying drugs, non-invasive ventilation, and maintaining the patient's nutritional status are crucial for managing ALS which can have non-motor symptoms as well.

A TRPV4 mutation caused Charcot-Marie-Tooth disease type 2C with scapuloperoneal muscular atrophy overlap syndrome and scapuloperoneal spinal muscular atrophy in one family: a case report and literature review

BackgroundCharcot-Marie-Tooth disease 2C (CMT2C) and scapuloperoneal spinal muscular atrophy (SPSMA) are different clinical phenotypes of TRPV4 mutation. The mutation of p.R316C has been reported to cause CMT2C and SPSMA separately.Case presentationHere, we reported a Chinese family harboring the same p.R316C variant, but with an overlap syndrome and different clinical manifestations. A 58-year-old man presented with severe scapula muscle atrophy, resulting in sloping shoulders. He also exhibited distinct muscle atrophy in his four limbs, particularly in the lower limbs. The sural nerve biopsy revealed severe loss of myelinated nerve fibers with scattered regenerating clusters and pseudo-onion bulbs. Nerve conduction study showed axon damage in both motor and sensory nerves. Sensory nerve action potentials could not be evoked in bilateral sural or superficial peroneal nerves. He was diagnosed with Charcot-Marie-Tooth disease type 2C and scapuloperoneal muscular atrophy overlap syndrome, whereas his 27-year-old son was born with clubfoot and clinodactyly. Electromyogram examination indicated chronic neurogenic changes and anterior horn cells involvement. Although there was no obvious weakness or sensory symptoms, early SPSMA could be considered for him.ConclusionsA literature review of the clinical characteristics in CMT2C and SPSMA patients with TRPV4 mutation suggested that our case was distinct due to the overlap syndrome and phenotype variation. Altogether, this case broadened the phenotype spectrum and provided the nerve biopsy pathological details of TRPV4-related neuropathies.

FOXO1 cooperates with C/EBPΔ and ATF4 to regulate skeletal muscle atrophy transcriptional program during fasting

Catabolic conditions, such as starvation, inactivity, and cancer cachexia, induce Forkhead box O (FOXO) transcription factor(s) expression and severe muscle atrophy via the induction of ubiquitin–proteasome system-mediated muscle proteolysis, resulting in frailty and poor quality of life. Although FOXOs are clearly essential for the induction of muscle atrophy, it is unclear whether there are other factors involved in the FOXO-mediated transcriptional regulation. As such, we identified FOXO–CCAAT/enhancer binding protein Δ (C/EBPΔ) signaling pathway as a novel proteolytic pathway. By comparing the gene expression profiles of FOXO1-transgenic (gain-of-function model) and FOXO1,3a,4–/–(loss-of-function model) mice, we identified several novel FOXO1-target genes in skeletal muscle including Redd1, Sestrin1, Castor2, Chac1, Depp1, Lat3, as well as C/EBPΔ. During starvation, C/EBPΔ abundance was increased in a FOXOs-dependent manner. Notably, knockdown of C/EBPΔ prevented the induction of the ubiquitin–proteasome system and decrease of myofibers in FOXO1-activated myotubes. Conversely, C/EBPΔ overexpression in primary myotubes induced myotube atrophy. Furthermore, we demonstrated that FOXO1 enhances the promoter activity of target genes in cooperation with C/EBPΔ and ATF4. This research comprehensively identifies novel FOXO1 target genes in skeletal muscle and clarifies the pathophysiological role of FOXO1, a master regulator of skeletal muscle atrophy. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.