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Mayo Clinic Proceedings Jan 2024Parsonage-Turner syndrome and hereditary brachial plexus neuropathy (HBPN) present with indistinguishable attacks of rapid-onset severe shoulder and arm pain, disabling... (Review)
Review
Parsonage-Turner syndrome and hereditary brachial plexus neuropathy (HBPN) present with indistinguishable attacks of rapid-onset severe shoulder and arm pain, disabling weakness, and early muscle atrophy. Their combined incidence ranges from 3 to 100 in 100,000 persons per year. Dominant mutations of SEPT9 are the only known mutations responsible for HBPN. Parsonage and Turner termed the disorder "brachial neuralgic amyotrophy," highlighting neuropathic pain and muscle atrophy. Modern electrodiagnostic and imaging testing assists the diagnosis in distinction from mimicking disorders. Shoulder and upper limb nerves outside the brachial plexus are commonly affected including the phrenic nerve where diaphragm ultrasound improves diagnosis. Magnetic resonance imaging can show multifocal T2 nerve and muscle hyperintensities with nerve hourglass swellings and constrictions identifiable also by ultrasound. An inflammatory immune component is suggested by nerve biopsies and associated infectious, immunization, trauma, surgery, and childbirth triggers. High-dose pulsed steroids assist initial pain control; however, weakness and subsequent pain are not clearly responsive to steroids and instead benefit from time, physical therapy, and non-narcotic pain medications. Recurrent attacks in HBPN are common and prophylactic steroids or intravenous immunoglobulin may reduce surgical- or childbirth-induced attacks. Rehabilitation focusing on restoring functional scapular mechanics, energy conservation, contracture prevention, and pain management are critical. Lifetime residual pain and weakness are rare with most making dramatic functional recovery. Tendon transfers can be used when recovery does not occur after 18 months. Early neurolysis and nerve grafts are controversial. This review provides an update including new diagnostic tools, new associations, and new interventions crossing multiple medical disciplines.
Topics: Humans; Brachial Plexus Neuritis; Pain; Muscular Atrophy; Steroids
PubMed: 38176820
DOI: 10.1016/j.mayocp.2023.06.011 -
The American Journal of Sports Medicine Oct 2023Progressive fatty infiltration and muscle atrophy after rotator cuff tears lead to tendon repair failure and poor outcomes. Fibro-adipogenic progenitors (FAPs) are...
BACKGROUND
Progressive fatty infiltration and muscle atrophy after rotator cuff tears lead to tendon repair failure and poor outcomes. Fibro-adipogenic progenitors (FAPs) are involved in fatty infiltration and muscle homeostasis of skeletal muscle. Inducing FAP differentiation into brown adipocyte-like "beige adipocytes" suppresses fatty infiltration and muscle atrophy.
HYPOTHESIS
Parathyroid hormone (PTH) suppresses fatty infiltration and muscle atrophy after rotator cuff tears in a rat model by browning of FAPs.
STUDY DESIGN
Controlled laboratory study.
METHODS
PTH was administered subcutaneously for 4 or 8 weeks to a rotator cuff tear model in rats. After treatment, fatty infiltration of supraspinatus muscles was assessed using Oil Red O staining and muscle atrophy using wet muscle weight and muscle fiber cross-sectional area. Costaining of platelet-derived growth factor receptor α (FAP marker) and uncoupling protein 1 (browning marker) was performed to confirm FAP browning by PTH. Mouse-isolated FAPs were cultured with PTH and evaluated for browning-related gene expression and adipogenic differentiation using BODIPY staining. Myogenic differentiation of C2C12 myoblasts was evaluated using coculture of PTH-treated browning FAPs with C2C12.
RESULTS
PTH inhibited fatty infiltration after rotator cuff tear at 8 weeks. Rotator cuff wet muscle loss of PTH-treated rats was inhibited at 4 and 8 weeks. Furthermore, PTH-treated rats demonstrated larger myofiber cross-sectional area than did untreated rats at 4 and 8 weeks. Costaining indicated colocalization of platelet-derived growth factor receptor α and uncoupling protein 1 and promoted PTH-induced FAP browning. PTH increased the expression of browning-related genes in FAPs and suppressed fat droplet accumulation in vitro. Coculture with PTH-treated FAPs promoted C2C12 cell differentiation into myotubes.
CONCLUSION
PTH induced FAP-derived beige adipocytes by upregulating browning-related gene expression, and the browning effect of PTH on FAPs inhibited fatty infiltration and muscle atrophy in the rat rotator cuff tear model. PTH might have potential as a therapeutic drug for fatty infiltration and muscle atrophy after rotator cuff tears.
CLINICAL RELEVANCE
PTH may expand treatment options for rotator cuff tears by reducing fatty infiltration and muscle atrophy after rotator cuff tears by browning of FAPs.
Topics: Mice; Rats; Animals; Rotator Cuff Injuries; Rodentia; Uncoupling Protein 1; Rotator Cuff; Muscular Atrophy; Receptors, Platelet-Derived Growth Factor; Adipose Tissue
PubMed: 37621014
DOI: 10.1177/03635465231190389 -
JCI Insight Sep 2023Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now... (Review)
Review
Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of SMA; however, they are not curative, likely due to a combination of imperfect treatment timing, inadequate SMN augmentation, and failure to optimally target relevant organs. Here, we consider the implications of imperfect treatment administration, focusing specifically on outcomes for skeletal muscle. We examine the evidence that muscle plays a contributing role in driving neuromuscular dysfunction in SMA. Next, we discuss how SMN might regulate the health of myofibers and their progenitors. Finally, we speculate on therapeutic outcomes of failing to raise muscle SMN to healthful levels and present strategies to restore function to this tissue to ensure better treatment results.
Topics: Child; Humans; Muscular Atrophy, Spinal; Neuromuscular Diseases; Muscle, Skeletal; Phenotype; Transcription Factors
PubMed: 37737261
DOI: 10.1172/jci.insight.171878 -
Journal of Cachexia, Sarcopenia and... Feb 2024Muscle aging is associated with a consistent decrease in the ability of muscle tissue to regenerate following intrinsic muscle degradation, injury or overuse....
BACKGROUND
Muscle aging is associated with a consistent decrease in the ability of muscle tissue to regenerate following intrinsic muscle degradation, injury or overuse. Age-related imbalance of protein synthesis and degradation, mainly regulated by AKT/mTOR pathway, leads to progressive loss of muscle mass. Maintenance of anabolic and regenerative capacities of skeletal muscles may be regarded as a therapeutic option for sarcopenia and other muscle wasting diseases. Our previous studies have demonstrated that BIO101, a pharmaceutical grade 20-hydroxyecdysone, increases protein synthesis through the activation of MAS receptor involved in the protective arm of renin-angiotensin-aldosterone system. The purpose of the present study was to assess the anabolic and pro-differentiating properties of BIO101 on C2C12 muscle cells in vitro and to investigate its effects on adult and old mice models in vivo.
METHODS
The effects of BIO101 on C2C12 differentiation were assessed using myogenic transcription factors and protein expression of major kinases of AKT/mTOR pathway by Western blot. The in vivo effects of BIO101 have been investigated in BIO101 orally-treated (50 mg/kg/day) adult mice (3 months) for 28 days. To demonstrate potential beneficial effect of BIO101 treatment in a sarcopenic mouse model, we use orally treated 22-month-old C57Bl6/J mice, for 14 weeks with vehicle or BIO101. Mice body and muscle weight were recorded. Physical performances were assessed using running capacity and muscle contractility tests.
RESULTS
Anabolic properties of BIO101 were confirmed by the rapid activation of AKT/mTOR, leading to an increase of C2C12 myotubes diameters (+26%, P < 0.001). Pro-differentiating effects of BIO101 on C2C12 myoblasts were revealed by increased expression of muscle-specific differentiation transcription factors (MyoD, myogenin), resulting in increased fusion index and number of nuclei per myotube (+39% and +53%, respectively, at day 6). These effects of BIO101 were like those of angiotensin (1-7) and were abolished with the use of A779, a MAS receptor specific antagonist. Chronic BIO101 oral treatment induced AKT/mTOR activation and anabolic effects accompanied with improved physical performances in adult and old animals (maximal running distance and maximal running velocity).
CONCLUSIONS
Our data suggest beneficial anabolic and pro-differentiating effects of BIO101 rendering BIO101 a potent drug candidate for treating sarcopenia and possibly other muscle wasting disorders.
Topics: Mice; Animals; Sarcopenia; Proto-Oncogene Proteins c-akt; Muscle, Skeletal; Muscular Diseases; Muscular Atrophy; TOR Serine-Threonine Kinases; Myoblasts; Transcription Factors
PubMed: 38064183
DOI: 10.1002/jcsm.13326 -
Seminars in Cell & Developmental Biology Jul 2023Mitochondria play a major role in apoptotic signaling. In addition to its role in eliminating dysfunctional cells, mitochondrial apoptotic signaling is implicated as a... (Review)
Review
Mitochondria play a major role in apoptotic signaling. In addition to its role in eliminating dysfunctional cells, mitochondrial apoptotic signaling is implicated as a key component of myogenic differentiation and skeletal muscle atrophy. For example, the activation of cysteine-aspartic proteases (caspases; CASP's) can aid in the initial remodeling stages of myogenic differentiation by cleaving protein kinases, transcription factors, and cytoskeletal proteins. Precise regulation of these signals is needed to prevent excessive cell disassemble and subsequent cell death. During skeletal muscle atrophy, the activation of CASP's and mitochondrial derived nucleases participate in myonuclear fragmentation, a potential loss of myonuclei, and cleavage of contractile structures within skeletal muscle. The B cell leukemia/lymphoma 2 (BCL2) family of proteins play a significant role in regulating myogenesis and skeletal muscle atrophy by governing the initiating steps of mitochondrial apoptotic signaling. This review discusses the role of mitochondrial apoptotic signaling in skeletal muscle remodeling during myogenic differentiation and skeletal muscle pathological states, including aging, disuse, and muscular dystrophy.
Topics: Humans; Apoptosis; Caspases; Muscle Development; Muscle, Skeletal; Muscular Atrophy; Mitochondria, Muscle
PubMed: 35241367
DOI: 10.1016/j.semcdb.2022.01.011 -
International Immunopharmacology Nov 2023Cachexia, marked by muscle atrophy, poses substantial challenges for prevention and treatment. This study delves into the unclear role of butyrate, a gut microbiota...
The metabolite butyrate produced by gut microbiota inhibits cachexia-associated skeletal muscle atrophy by regulating intestinal barrier function and macrophage polarization.
OBJECTIVE
Cachexia, marked by muscle atrophy, poses substantial challenges for prevention and treatment. This study delves into the unclear role of butyrate, a gut microbiota metabolite, in cachexia by examining gut microbiota and short-chain fatty acid (SCFA) profiles in human and mouse fecal samples.
METHODS
We analyzed cachexia-associated gut microbiota and SCFA profiles using 16S rRNA sequencing and metabolomic techniques. Mouse cachexia models were developed with C26 cells, and LPS was used to induce muscle cell atrophy in C2C12 cells. We evaluated butyrate's in vivo effects on intestinal health, muscle preservation, inflammation, and macrophage activity. In vitro studies focused on butyrate's influence on macrophage polarization and the subsequent effects on muscle cells.
RESULTS
Both cachexia patients and mice exhibited gut microbiota imbalances, irregular butyrate concentrations, and a decline in butyrate-producing bacteria. In vivo tests showed that butyrate counteract cachexia-induced muscle atrophy by adjusting the Akt/mTOR/Foxo3a and Fbox32/Trim63 pathways. These butyrate also bolstered intestinal barrier integrity, minimized endotoxin migration, and mitigated oxidative stress. Furthermore, butyrate curtailed inflammation and macrophage penetration in muscles. In vitro experimental results demonstrate that butyrate inhibit macrophage polarization towards the M1 phenotype and promote polarization towards the M2 phenotype. Both M1 and M2 macrophages influence the aforementioned pathways and oxidative stress, participating in the regulation of muscle cell atrophy.
CONCLUSION
Our study delineates the intricate interplay between gut microbiota dysbiosis, butyrate fluctuations, and cachexia progression. Butyrate not only reinforces the intestinal barrier but also orchestrates macrophage polarization, mitigating muscle atrophy and averting cachexia-induced muscle deterioration. Concurrently, the M1 and M2 macrophages play pivotal roles in modulating skeletal muscle cell atrophy. This highlights the potential of utilizing the gut-derived metabolite butyrate as a promising therapeutic approach for addressing cachexia-related issues.
Topics: Humans; Animals; Mice; Butyrates; Cachexia; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Inflammation; Fatty Acids, Volatile; Disease Models, Animal; Macrophages; Muscular Atrophy; Muscle, Skeletal
PubMed: 37804658
DOI: 10.1016/j.intimp.2023.111001 -
Journal of Advanced Research Aug 2023Myogenic differentiation plays an important role in pathophysiological processes including muscle injury and regeneration, as well as muscle atrophy. A novel type of...
INTRODUCTION
Myogenic differentiation plays an important role in pathophysiological processes including muscle injury and regeneration, as well as muscle atrophy. A novel type of posttranslational modification, crotonylation, has been reported to play a role in stem cell differentiation and disease. However, the role of crotonylation in myogenic differentiation has not been clarified.
OBJECTIVES
This study aims to find the role of crotonylation during myogenic differentiation and explore whether it is a potential target in myogenic dysfunction disease.
METHODS
C2C12 cell line and skeletal muscle mesenchymal progenitors of Mus musculus were used for myogenic process study in vitro, while muscle injury model of mice was used for in vivo muscle regeneration study. Mass spectrometry favored in discovery of potential target protein of crotonylation and its specific sites.
RESULTS
We confirmed the gradual decrease in total protein crotonylation level during muscle differentiation and found decreased crotonylation of AKT1, which facilitated an increase in AKT1 phosphorylation. Then we verified that crotonylation of AKT1 at specific sites weakened its binding with PDK1 and impaired its phosphorylation. In addition, we found that increased expression of the crotonylation eraser HDAC3 decreased AKT1 crotonylation levels during myogenic differentiation, jointly promoting myogenic differentiation.
CONCLUSION
Our study highlights the important role of decrotonylation of AKT1 in the process of muscle differentiation, where it aids the phosphorylation and activation of AKT1 and promotes myogenic differentiation. This is of great significance for exploring the pathophysiological process of muscle injury repair and sarcopenia.
Topics: Animals; Mice; Cell Differentiation; Cell Line; Muscle, Skeletal; Muscular Atrophy; Phosphorylation
PubMed: 36265762
DOI: 10.1016/j.jare.2022.10.005 -
International Journal of Molecular... Nov 2023Epigenetic changes contribute to the profound alteration in the transcriptional program associated with the onset and progression of muscle wasting in several... (Review)
Review
Epigenetic changes contribute to the profound alteration in the transcriptional program associated with the onset and progression of muscle wasting in several pathological conditions. Although HDACs and their inhibitors have been extensively studied in the field of muscular dystrophies, the potential of epigenetic inhibitors has only been marginally explored in other disorders associated with muscle atrophy, such as in cancer cachexia and sarcopenia. BET inhibitors represent a novel class of recently developed epigenetic drugs that display beneficial effects in a variety of diseases beyond malignancies. Based on the preliminary in vitro and preclinical data, HDACs and BET proteins contribute to the pathogenesis of cancer cachexia and sarcopenia, modulating processes related to skeletal muscle mass maintenance and/or metabolism. Thus, epigenetic drugs targeting HDACs and BET proteins may emerge as promising strategies to reverse the catabolic phenotype associated with cachexia and sarcopenia. Further preclinical studies are warranted to delve deeper into the molecular mechanisms associated with the functions of HDACs and BET proteins in muscle atrophy and to establish whether their epigenetic inhibitors represent a prospective therapeutic avenue to alleviate muscle wasting.
Topics: Humans; Antineoplastic Agents; Cachexia; Epigenesis, Genetic; Muscle, Skeletal; Muscular Atrophy; Neoplasms; Proteins; Sarcopenia; Histone Deacetylases
PubMed: 38003594
DOI: 10.3390/ijms242216404 -
Biochimica Et Biophysica Acta.... Mar 2024Cigarette smoke (CS) is the major risk factor for chronic obstructive pulmonary disease (COPD), and sarcopenia is one of the significant comorbidities of COPD. However,...
Cigarette smoke (CS) is the major risk factor for chronic obstructive pulmonary disease (COPD), and sarcopenia is one of the significant comorbidities of COPD. However, the pathogenesis of CS-related deficient skeletal muscle regeneration has yet to be clarified. The impact of CS on myoblast differentiation was examined, and then we determined which HDAC influenced the myogenic process and muscle atrophy in vitro and in vivo. Finally, we further investigated the potential mechanisms via RNA sequencing. Long-term CS exposure activated skeletal muscle primary satellite cells (SCs) while inhibiting differentiation, and defective myogenesis was also observed in C2C12 cells treated with CS extract (CSE). The level of HDAC9 changed in vitro and in vivo in CS exposure models as well as COPD patients, as detected by bioinformatics analysis. Our data showed that CSE impaired myogenic capacity and myotube formation in C2C12 cells via HDAC9. Moreover, inhibition of HDAC9 in mice exposed to CS prevented skeletal muscle dysfunction and promoted SC differentiation. The results of RNA-Seq analysis and verification indicated that HDAC9 knockout improved muscle differentiation in CS-exposed mice, probably by acting on the AKT/mTOR pathway and inhibiting the P53/P21 pathway. More importantly, the serum of HDAC9 KO mice exposed to CS alleviated the differentiation impairment of C2C12 cells caused by serum intervention in CS-exposed mice, and this effect was inhibited by LY294002 (an AKT/mTOR pathway inhibitor). These results suggest that HDAC9 plays an essential role in the defective regeneration induced by chronic exposure to CS.
Topics: Humans; Animals; Mice; Proto-Oncogene Proteins c-akt; Cigarette Smoking; Pulmonary Disease, Chronic Obstructive; Muscular Atrophy; Muscle, Skeletal; TOR Serine-Threonine Kinases; Histone Deacetylases; Repressor Proteins
PubMed: 38218381
DOI: 10.1016/j.bbadis.2024.167023 -
FASEB Journal : Official Publication of... Sep 2023Oxidative stress plays an important role in skeletal muscle atrophy during cancer cachexia, and more glycolytic muscles are preferentially affected. Sequestosome1/SQSTM1...
Oxidative stress plays an important role in skeletal muscle atrophy during cancer cachexia, and more glycolytic muscles are preferentially affected. Sequestosome1/SQSTM1 (i.e., p62), particularly when phosphorylated at Ser 349 (Ser 351 in mice), competitively binds to the Kelch-like ECH-associated protein 1 (Keap1) activating Nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 then stimulates the transcription of antioxidant/electrophile-responsive elements in target genes. However, a potential role for p62 in the protection of muscle wasting in cachexia remains to be determined. Here, using the well-established cachexia-inducing model of Lewis Lung Carcinoma (LLC) in mice we demonstrate higher expression of antioxidant proteins (i.e., NQO1, HO-1, GSTM1, CuZnSOD, MnSOD, and EcSOD) in the more oxidative and cachexia resistant soleus muscle than in the more glycolytic and cachexia prone extensor digitorum longus muscle. This was accompanied by higher p62 (total and phosphorylated) and nuclear Nrf2 levels in the soleus, which were paralleled by higher expression of proteins known to either phosphorylate or promote p62 phosphorylation (i.e., NBR1, CK1, PKCδ, and TAK1). Muscle-specific p62 gain-of-function (i.e., in p62 mTg mice) activated Nrf2 nuclear translocation and increased the expression of multiple antioxidant proteins (i.e., CuZnSOD, MnSOD, EcSOD, NQO1, and GSTM1) in glycolytic muscles. Interestingly, skeletal muscle Nrf2 haplodeficiency blunted the increases of most of these proteins (i.e., CuZnSOD, EcSOD, and NQO1) suggesting that muscle p62 stimulates antioxidant protein expression also via additional, yet to be determined mechanisms. Of note, p62 gain-of-function mitigated glycolytic muscle wasting in LLC-affected mice. Collectively, our findings identify skeletal muscle p62 as a potential therapeutic target for cancer cachexia.
Topics: Animals; Mice; Antioxidants; Cachexia; Carcinoma, Lewis Lung; Kelch-Like ECH-Associated Protein 1; Muscle, Skeletal; Muscular Atrophy; NF-E2-Related Factor 2; Sequestosome-1 Protein
PubMed: 37624620
DOI: 10.1096/fj.202300349R