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Nature Communications Jun 2024Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of...
Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.
Topics: Animals; Oxidative Stress; Interferon-gamma; Myositis; Humans; Female; Reactive Oxygen Species; Mice; Mice, Inbred NOD; Mitochondria; Muscle, Skeletal; Disease Models, Animal; Mitochondria, Muscle; Mice, Knockout; Myoblasts
PubMed: 38926363
DOI: 10.1038/s41467-024-49460-1 -
Poultry Science May 2024Wooden Breast (WB) abnormality represents one of the major challenges that the poultry industry has faced in the last 10 years. Despite the enormous progress in...
Wooden Breast (WB) abnormality represents one of the major challenges that the poultry industry has faced in the last 10 years. Despite the enormous progress in understanding the mechanisms underlying WB, the precise initial causes remain to be clarified. In this scenario, the present research is intended to characterize the gene expression profiles of broiler Pectoralis major muscles affected by WB, comparing them to the unaffected counterpart, to provide new insights into the biological mechanisms underlying this defect and potentially identifying novel genes likely involved in its occurrence. To this purpose, data obtained in a previous study through the RNA-sequencing technology have been used to identify differentially expressed genes (DEGs) between 6 affected and 5 unaffected broilers' breast muscles, by using the newest reference genome assembly for Gallus gallus (GRCg7b). Also, to deeply investigate molecular and biological pathways involved in the WB progression, pathways analyses have been performed. The results achieved through the differential gene expression analysis mainly evidenced the downregulation of glycogen metabolic processes, gluconeogenesis, and tricarboxylic acid cycle in WB muscles, thus corroborating the evidence of a dysregulated energy metabolism characterizing breasts affected by this abnormality. Also, genes related to hypertrophic muscle growth have been identified as differentially expressed (e.g., WFIKKN1). Together with that, a downregulation of genes involved in mitochondrial biogenesis and functionality has been detected. Among them, PPARGC1A and PPARGC1B chicken genes are particularly noteworthy. These genes not only have essential roles in regulating mitochondrial biogenesis but also play pivotal roles in maintaining glucose and energy homeostasis. In view of that, their downregulation in WB-affected muscle may be considered as potentially related to both the mitochondrial dysfunction and altered glucose metabolism in WB muscles, and their key involvement in the molecular alterations characterizing this muscular abnormality might be hypothesized.
PubMed: 38908127
DOI: 10.1016/j.psj.2024.103902 -
BioRxiv : the Preprint Server For... May 2024Pathogenic variants in were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key...
Pathogenic variants in were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants in with skeletal muscle dysfunction is unclear. We knocked down in mouse skeletal myoblasts, knocked down in Drosophila, and expressed three pathogenic variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in knockdown mouse myoblasts. deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of in Drosophila led to lethality. Overexpression of reference cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.
PubMed: 38903061
DOI: 10.1101/2024.05.06.591934 -
Biochimica Et Biophysica Acta.... Jun 2024Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays...
Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays a variety of roles in the cell including the degradation of proteins and the maintenance of mitochondrial homeostasis, integrity, and biogenesis. In 2001, the R275W mutation in the PRKN gene was identified in two unrelated families with a multigenerational history of postural tremor, dystonia and parkinsonism. Drosophila models of Parkin R275W showed selective and progressive degeneration of dopaminergic neuronal clusters, mitochondrial abnormalities, and prominent climbing defects. In the Prkn mouse orthologue, the amino acid R274 corresponds to human R275. Here we described an age-related motor impairment and a muscle phenotype in R274W +/+ mice. In vitro, Parkin R274W mutation correlates with abnormal myoblast differentiation, mitochondrial defects, and alteration in mitochondrial mRNA and protein levels. Our data suggest that the Parkin R274W mutation may impact mitochondrial physiology and eventually myoblast proliferation and differentiation.
PubMed: 38878834
DOI: 10.1016/j.bbadis.2024.167302 -
Annals of Indian Academy of Neurology Jun 2024
PubMed: 38856162
DOI: 10.4103/aian.aian_76_24 -
Poultry Science May 2024This study aims to provide new insight on the association between the development of wooden breast myopathy and mitochondrial and glycolytic activity under oxidative...
This study aims to provide new insight on the association between the development of wooden breast myopathy and mitochondrial and glycolytic activity under oxidative stress. Myopathic muscle had higher oxidative stress together with altered glycolytic metabolism and tricarboxylic acid (TCA) cycle. This was evidenced by significantly elevated antioxidant enzyme activities (catalase, superoxide dismutase, and glutathione peroxidase), decreased citrate synthase activity and postmortem glycolytic potential with increasing wooden breast severity. In addition, affected muscles also exhibited higher initial and ultimate pH values as well as reduced total glucose and lactate contents. Citrate synthase activity was negatively correlated to antioxidant enzyme activities. Taken together, we propose that the development of the wooden breast lesion is a chronic process that may be related to the failure of muscle fibers to defend against the excessively generated oxidative products promoted by mitochondrial damage accompanied by impaired TCA cycle. Furthermore, there was a positive correlation between citrate synthase activity and glycolytic potential, which suggests that the wooden breast condition is linked to the overall altered energy metabolism of the muscle, including the oxidative phosphorylation and glycolytic pathways.
PubMed: 38843563
DOI: 10.1016/j.psj.2024.103877 -
Journal of Animal Science and... Jun 2024Wooden breast (WB) myopathy is a common myopathy found in commercial broiler chickens worldwide. Histological examination has revealed that WB myopathy is accompanied by...
BACKGROUND
Wooden breast (WB) myopathy is a common myopathy found in commercial broiler chickens worldwide. Histological examination has revealed that WB myopathy is accompanied by damage to the pectoralis major (PM) muscle. However, the underlying mechanisms responsible for the formation of WB in broilers have not been fully elucidated. This study aimed to investigate the potential role of hypoxia-mediated programmed cell death (PCD) in the formation of WB myopathy.
RESULTS
Histological examination and biochemical analysis were performed on the PM muscle of the control (CON) and WB groups. A significantly increased thickness of the breast muscle in the top, middle, and bottom portions (P<0.01) was found along with pathological structure damage of myofibers in the WB group. The number of capillaries per fiber in PM muscle, and the levels of pO and sO in the blood, were significantly decreased (P < 0.01), while the levels of pCO and TCO in the blood were significantly increased (P < 0.05), suggesting hypoxic conditions in the PM muscle of the WB group. We further evaluated the PCD-related pathways including autophagy, apoptosis, and necroptosis to understand the consequence response to enhanced hypoxic conditions in the PM muscle of birds with WB. The ratio of LC3 II to LC3 I, and the autophagy-related factors HIF-1α, BNIP3, Beclin1, AMPKα, and ULK1 at the mRNA and protein levels, were all significantly upregulated (P < 0.05), showing that autophagy occurred in the PM muscle of the WB group. The apoptotic index, as well as the expressions of Bax, Cytc, caspase 9, and caspase 3, were significantly increased (P < 0.05), whereas Bcl-2 was significantly decreased (P < 0.05) in the WB-affected PM muscle, indicating the occurrence of apoptosis mediated by the mitochondrial pathway. Additionally, the expressions of necroptosis-related factors RIP1, RIP3, and MLKL, as well as NF-κB and the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, were all significantly enhanced (P < 0.05) in the WB-affected PM muscle.
CONCLUSIONS
The WB myopathy reduces blood supply and induces hypoxia in the PM muscle, which is closely related to the occurrence of PCD including apoptosis, autophagy, and necroptosis within myofibers, and finally leads to abnormal muscle damage and the development of WB in broilers.
PubMed: 38840220
DOI: 10.1186/s40104-024-01036-1 -
BMC Genomics May 2024Mitochondrial diseases (MDs) can be caused by single nucleotide variants (SNVs) and structural variants (SVs) in the mitochondrial genome (mtDNA). Presently, identifying...
BACKGROUND
Mitochondrial diseases (MDs) can be caused by single nucleotide variants (SNVs) and structural variants (SVs) in the mitochondrial genome (mtDNA). Presently, identifying deletions in small to medium-sized fragments and accurately detecting low-percentage variants remains challenging due to the limitations of next-generation sequencing (NGS).
METHODS
In this study, we integrated targeted long-range polymerase chain reaction (LR-PCR) and PacBio HiFi sequencing to analyze 34 participants, including 28 patients and 6 controls. Of these, 17 samples were subjected to both targeted LR-PCR and to compare the mtDNA variant detection efficacy.
RESULTS
Among the 28 patients tested by long-read sequencing (LRS), 2 patients were found positive for the m.3243 A > G hotspot variant, and 20 patients exhibited single or multiple deletion variants with a proportion exceeding 4%. Comparison between the results of LRS and NGS revealed that both methods exhibited similar efficacy in detecting SNVs exceeding 5%. However, LRS outperformed NGS in detecting SNVs with a ratio below 5%. As for SVs, LRS identified single or multiple deletions in 13 out of 17 cases, whereas NGS only detected single deletions in 8 cases. Furthermore, deletions identified by LRS were validated by Sanger sequencing and quantified in single muscle fibers using real-time PCR. Notably, LRS also effectively and accurately identified secondary mtDNA deletions in idiopathic inflammatory myopathies (IIMs).
CONCLUSIONS
LRS outperforms NGS in detecting various types of SNVs and SVs in mtDNA, including those with low frequencies. Our research is a significant advancement in medical comprehension and will provide profound insights into genetics.
Topics: Humans; DNA, Mitochondrial; High-Throughput Nucleotide Sequencing; Mitochondrial Diseases; Female; Male; Sequence Analysis, DNA; Adult; Middle Aged; Polymorphism, Single Nucleotide; Polymerase Chain Reaction
PubMed: 38822239
DOI: 10.1186/s12864-024-10433-9 -
Frontiers in Cell and Developmental... 2024Sporadic inclusion body myositis (sIBM) is a distinct subcategory of Idiopathic Inflammatory Myopathies (IIM), characterized by unique pathological features such as... (Review)
Review
Sporadic inclusion body myositis (sIBM) is a distinct subcategory of Idiopathic Inflammatory Myopathies (IIM), characterized by unique pathological features such as muscle inflammation, rimmed vacuoles, and protein aggregation within the myofibers. Although hyperactivation of the immune system is widely believed as the primary cause of IIM, it is debated whether non-immune tissue dysfunction might contribute to the disease's onset as patients with sIBM are refractory to conventional immunosuppressant treatment. Moreover, the findings that mitochondrial dysfunction can elicit non-apoptotic programmed cell death and the subsequent immune response further support this hypothesis. Notably, abnormal mitochondrial structure and activities are more prominent in the muscle of sIBM than in other types of IIM, suggesting the presence of defective mitochondria might represent an overlooked contributor to the disease onset. The large-scale mitochondrial DNA deletion, aberrant protein aggregation, and slowed organelle turnover have provided mechanistic insights into the genesis of impaired mitochondria in sIBM. This article reviews the disease hallmarks of sIBM, the plausible contributors of mitochondrial damage in the sIBM muscle, and the immunological responses associated with mitochondrial perturbations. Additionally, the potential application of mitochondrial-targeted chemicals as a new treatment strategy to sIBM is explored and discussed.
PubMed: 38808223
DOI: 10.3389/fcell.2024.1403463 -
American Journal of Ophthalmology Case... Jun 2024To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of gene variant m.8969G > A.
PURPOSE
To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of gene variant m.8969G > A.
OBSERVATIONS
A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in , m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy.
CONCLUSIONS AND IMPORTANCE
Rare variants in can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.
PubMed: 38756953
DOI: 10.1016/j.ajoc.2024.102070