bims-musmir 2024-11-24 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–11–24
sixteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Post-sepsis chronic muscle weakness can be prevented by pharmacological protection of mitochondria.
Impact of Ageing and Disuse on Neuromuscular Junction and Mitochondrial Function and Morphology: Current Evidence and Controversies.
Transcriptomic analysis of skeletal muscle regeneration across mouse lifespan identifies altered stem cell states.
The mitochondrial-targeted peptide therapeutic elamipretide improves cardiac and skeletal muscle function during aging without detectable changes in tissue epigenetic or transcriptomic age.
Ultrastructural alterations and mitochondrial dysfunction in skeletal muscle of peripheral artery disease patients: implications for early therapeutic interventions.
Mapping aged stem cell states associated with decline in skeletal muscle regeneration.
Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.
Mitochondrial Pathogenic Mutations and Expression Pattern of Oxidative Phosphorylation Genes in COVID-19 Patients.
Ucp1 Ablation Improves Skeletal Muscle Glycolytic Function in Aging Mice.
AMPK regulates the maintenance and remodelling of the neuromuscular junction.
Exploring differential miRNA expression profiles in muscular and visceral adipose tissue of patients with severe obesity.
Overexpression of autophagy enhancer PACER/RUBCNL in neurons accelerates disease in the SOD1G93A ALS mouse model.
Regulating translation in aging: from global to gene-specific mechanisms.
From Mild Cases to Critical Cases of COVID-19: The Role of Genes in Inflammasome and Mitochondrial Dynamics.
Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis.
Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action.

Mol Med. 2024 Nov 19. 30(1): 221

Post-sepsis chronic muscle weakness can be prevented by pharmacological protection of mitochondria.

Meagan S Kingren, Alexander R Keeble, Alyson M Galvan-Lara, Jodi M Ogle, Zoltán Ungvári, Daret K St Clair, Timothy A Butterfield, Allison M Owen, Christopher S Fry, Samir P Patel, Hiroshi Saito.

   BACKGROUND: Sepsis, mainly caused by bacterial infections, is the leading cause of in-patient hospitalizations. After discharge, most sepsis survivors suffer from long-term medical complications, particularly chronic skeletal muscle weakness. To investigate this medical condition in detail, we previously developed a murine severe sepsis-survival model that exhibits long-term post-sepsis skeletal muscle weakness. While mitochondrial abnormalities were present in the skeletal muscle of the sepsis surviving mice, the relationship between abnormal mitochondria and muscle weakness remained unclear. Herein, we aimed to investigate whether mitochondrial abnormalities have a causal role in chronic post-sepsis muscle weakness and could thereby serve as a therapeutic target.
METHODS: Experimental polymicrobial abdominal sepsis was induced in 16-18 months old male and female mice using cecal slurry injection with subsequent antibiotic and fluid resuscitation. To evaluate the pathological roles of mitochondrial abnormalities in post-sepsis skeletal muscle weakness, we utilized a transgenic mouse strain overexpressing the mitochondria-specific antioxidant enzyme manganese superoxide dismutase (MnSOD). Following sepsis development in C57BL/6 mice, we evaluated the effect of the mitochondria-targeting synthetic tetrapeptide SS-31 in protecting mitochondria from sepsis-induced damage and preventing skeletal muscle weakness development. In vivo and in vitro techniques were leveraged to assess muscle function at multiple timepoints throughout sepsis development and resolution. Histological and biochemical analyses including bulk mRNA sequencing were used to detect molecular changes in the muscle during and after sepsis RESULTS: Our time course study revealed that post sepsis skeletal muscle weakness develops progressively after the resolution of acute sepsis and in parallel with the accumulation of mitochondrial abnormalities and changes in the mitochondria-related gene expression profile. Transgenic mice overexpressing MnSOD were protected from mitochondrial abnormalities and muscle weakness following sepsis. Further, pharmacological protection of mitochondria utilizing SS-31 during sepsis effectively prevented the later development of muscle weakness.
CONCLUSIONS: Our study revealed that the accumulation of mitochondrial abnormalities is the major cause of post-sepsis skeletal muscle weakness. Pharmacological protection of mitochondria during acute sepsis is a potential clinical treatment strategy to prevent post-sepsis muscle weakness.

Keywords:  Critical care illness; Mitochondrial myopathy; Muscle weakness; Post-sepsis syndrome

DOI:  https://doi.org/10.1186/s10020-024-00982-w
Ageing Res Rev. 2024 Nov 16. pii: S1568-1637(24)00404-5. [Epub ahead of print] 102586

Impact of Ageing and Disuse on Neuromuscular Junction and Mitochondrial Function and Morphology: Current Evidence and Controversies.

Evgeniia Motanova, Marco Pirazzini, Samuele Negro, Ornella Rossetto, Marco Narici.

  Inactivity and ageing can have a detrimental impact on skeletal muscle and the neuromuscular junction (NMJ). Decreased physical activity results in muscle atrophy, impaired mitochondrial function, and NMJ instability. Ageing is associated with a progressive decrease in muscle mass, deterioration of mitochondrial function in the motor axon terminals and in myofibres, NMJ instability and loss of motor units. Focusing on the impact of inactivity and ageing, this review examines the consequences on NMJ stability and the role of mitochondrial dysfunction, delving into their complex relationship with ageing and disuse. Evidence suggests that mitochondrial dysfunction can be a pathogenic driver for NMJ alterations, with studies revealing the role of mitochondrial defects in motor neuron degeneration and NMJ instability. Two perspectives behind NMJ instability are discussed: one is that mitochondrial dysfunction in skeletal muscle triggers NMJ deterioration, the other envisages dysfunction of motor terminal mitochondria as a primary contributor to NMJ instability. While evidence from these studies supports both perspectives on the relationship between NMJ dysfunction and mitochondrial impairment, gaps persist in the understanding of how mitochondrial dysfunction can cause NMJ deterioration. Further research, both in humans and in animal models, is essential for unravelling the mechanisms and potential interventions for age- and inactivity-related neuromuscular and mitochondrial alterations.

Keywords:  Ageing; Disuse; Mitochondrial Ca(2+); Mitochondrial dysfunction; Neuromuscular junction; Skeletal muscle

DOI:  https://doi.org/10.1016/j.arr.2024.102586
Nat Aging. 2024 Nov 22.

Transcriptomic analysis of skeletal muscle regeneration across mouse lifespan identifies altered stem cell states.

Lauren D Walter, Jessica L Orton, Ioannis Ntekas, Ern Hwei Hannah Fong, Viviana I Maymi, Brian D Rudd, Iwijn De Vlaminck, Jennifer H Elisseeff, Benjamin D Cosgrove.

In aging, skeletal muscle regeneration declines due to alterations in both myogenic and non-myogenic cells and their interactions. This regenerative dysfunction is not understood comprehensively or with high spatiotemporal resolution. We collected an integrated atlas of 273,923 single-cell transcriptomes and high-resolution spatial transcriptomic maps from muscles of young, old and geriatric mice (~5, 20 and 26 months old) at multiple time points following myotoxin injury. We identified eight immune cell types that displayed accelerated or delayed dynamics by age. We observed muscle stem cell states and trajectories specific to old and geriatric muscles and evaluated their association with senescence by scoring experimentally derived and curated gene signatures in both single-cell and spatial transcriptomic data. This revealed an elevation of senescent-like muscle stem cell subsets within injury zones uniquely in aged muscles. This Resource provides a holistic portrait of the altered cellular states underlying muscle regenerative decline across mouse lifespan.

DOI: https://doi.org/10.1038/s43587-024-00756-3
bioRxiv. 2024 Oct 31. pii: 2024.10.30.620676. [Epub ahead of print]

The mitochondrial-targeted peptide therapeutic elamipretide improves cardiac and skeletal muscle function during aging without detectable changes in tissue epigenetic or transcriptomic age.

Wayne Mitchell, Gavin Pharaoh, Alexander Tyshkovskiy, Matthew Campbell, David J Marcinek, Vadim N Gladyshev.

Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondrial-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. ELAM is proposed to restore mitochondrial bioenergetic function by stabilizing inner membrane structure and increasing oxidative phosphorylation coupling and efficiency. Although ELAM treatment effectively attenuates physiological declines in multiple tissues in rodent aging models, it remains unclear whether these functional improvements correlate with favorable changes in molecular biomarkers of aging. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force are significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and heart failure in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.

DOI: https://doi.org/10.1101/2024.10.30.620676
EXCLI J. 2024 ;23 1208-1225

Ultrastructural alterations and mitochondrial dysfunction in skeletal muscle of peripheral artery disease patients: implications for early therapeutic interventions.

Dylan Wilburn, Emma Fletcher, Evlampia Papoutsi, William T Bohannon, Gleb Haynatzki, Bernd Zechmann, Yuqian Tian, Iraklis I Pipinos, Dimitrios Miserlis, Panagiotis Koutakis.

  Peripheral artery disease (PAD) is an atherosclerotic condition that impairs blood flow to the lower extremities, resulting in myopathy in affected skeletal muscles. Improving our understanding of PAD and developing novel treatment strategies necessitates a comprehensive examination of cellular structural alterations that occur in the muscles with disease progression. Here we aimed to employ electron microscopy to quantify skeletal muscle ultrastructural alterations responsible for the myopathy of PAD. Fifty-two participants (22 controls, 10 PAD Stage II, and 20 PAD Stage IV) were enrolled. Gastrocnemius biopsies were obtained to determine mitochondrial respiration and oxidative stress. Skeletal muscle sarcomere, mitochondria, lipid droplets, and sarcoplasm were assessed using transmission electron microscopy and focused ion beam scanning electron microscopy. Controls and PAD Stage II patients underwent walking performance tests: 6-minute walking test, 4-minute walking velocity, and maximum graded treadmill test. We identified several prominent ultrastructural modifications in PAD gastrocnemius, including reduced sarcomere dimensions, alterations in mitochondria number and localization, myofibrillar disorientation, changes in lipid droplets, and modifications in mitochondria-lipid droplet contact area. These changes correlated with impaired mitochondrial respiration and increased ROS production. We observed progressive deterioration in mitochondrial parameters across PAD stages. Stage II PAD showed impaired mitochondrial function and structure, while stage IV exhibited further deterioration, more pronounced structural alterations, and a decrease in mitochondrial content. The walking performance of Stage II PAD patients was significantly reduced. Our findings suggest that pathological mitochondria play a key role in the skeletal muscle dysfunction of PAD patients and represent an important target for therapeutic interventions aimed at improving clinical and functional outcomes in this patient population. Our data indicate that treatments should be implemented early and may include therapies designed to preserve and enhance mitochondrial biogenesis and respiration, optimize mitochondrial-lipid droplet interactions, or mitigate oxidative stress. Translational Perspective: Peripheral artery disease (PAD) is characterized by skeletal muscle and mitochondrial dysfunction. Ultrastructural changes in skeletal muscle myofibers and mitochondria morphology can provide significant information on the PAD pathophysiology. Here, we investigated skeletal muscle and mitochondria morphological and functional changes at the sarcomere level and across the disease progression and have found that sarcomere lengths and mitochondria count and function are associated with disease progression, indicating loss of skeletal muscle contractile and metabolic function. Ultrastructural changes in the PAD skeletal muscle can provide significant information in the development of new treatments.

Keywords:  intramyocellular lipids; mitochondria; muscle; peripheral artery disease; sarcomere atrophy; sarcoplasm

DOI:  https://doi.org/10.17179/excli2024-7592
Nat Aging. 2024 Nov 22.

Mapping aged stem cell states associated with decline in skeletal muscle regeneration.

DOI: https://doi.org/10.1038/s43587-024-00768-z
Ann Neurol. 2024 Nov 18.

Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.

Renjia Zhong, Demi L A Dionela, Nina Haeyeon Kim, Erin N Harris, John G Geisler, Lan Wei-LaPierre.

OBJECTIVE: Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.
METHODS: hSOD1G93A mice were treated with 0.5-1.0 mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18 weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18 weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1G93A mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.
RESULTS: DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18 weeks old in hSOD1G93A mice. Strikingly, symptomatic hSOD1G93A mice exhibited a period of recovery in running ability at 20 cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.
INTERPRETATION: Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2024.

DOI: https://doi.org/10.1002/ana.27140
Iran J Allergy Asthma Immunol. 2024 Jul 27. 23(4): 374-392

Mitochondrial Pathogenic Mutations and Expression Pattern of Oxidative Phosphorylation Genes in COVID-19 Patients.

Milad Shokuhi Nia, Dormohammad Kordi Tamandani, Mohammad Kazem Momeni, Zakaria Bameri.

  Mitochondrial missense mutations and pathogenic variants have been implicated in the pathogenesis of COVID-19. This study evaluated the role of mitochondrial DNA (mtDNA) mutations and changes in gene expression in the progression of COVID-19 and their correlation with clinical characteristics. Next-generation sequencing with high throughput was used to identify mtDNA mutations in 30 COVID-19 patients compared to 20 healthy controls. The potential impact of identified mutations on protein structure and stability was predicted using bioinformatic tools. Quantitative real-time polymerase chain reaction was employed to assess the expression levels of mtDNA-encoded genes involved in oxidative phosphorylation in COVID-19 patients and healthy controls. Correlations between gene expression levels, clinical parameters, including leukocyte, lymphocyte, neutrophil, and platelet count, as well as creatinine, alanine transaminase (ALT), aspartate transaminase (AST), and blood urea nitrogen (BUN) levels, and disease severity were analyzed. We found 8 different mtDNA mutations in ND1, ND5, CO3, ATP6, and CYB genes, which were predicted to alter amino acids and decrease protein stability. Two missense unique mutations, C9555T in CO3 and A12418T in ND5 were identified and correlated with Complexes I and IV, respectively. This downregulation was correlated with age, elevated levels of leukocytes, lymphocytes, neutrophils, platelets, creatinine, ALT, AST, and BUN, as well as disease severity. These findings suggest that mtDNA mutations and altered expression of oxidative phosphorylation genes contribute to mitochondrial dysfunction in COVID-19. Targeting mitochondrial dysfunction may represent a promising therapeutic strategy for COVID-19 treatment.

Keywords:  COVID-19; Mitochondria; Mitochondrial DNA; Mutation; Oxidative stress

DOI:  https://doi.org/10.18502/ijaai.v23i4.16212
Adv Sci (Weinh). 2024 Nov 21. e2411015

Ucp1 Ablation Improves Skeletal Muscle Glycolytic Function in Aging Mice.

Jin Qiu, Yuhan Guo, Xiaozhen Guo, Ziqi Liu, Zixuan Li, Jun Zhang, Yutang Cao, Jiaqi Li, Shuwu Yu, Sainan Xu, Juntong Chen, Dongmei Wang, Jian Yu, Mingwei Guo, Wenhao Zhou, Sainan Wang, Yiwen Wang, Xinran Ma, Cen Xie, Lingyan Xu.

  Muscular atrophy is among the systematic decline in organ functions in aging, while defective thermogenic fat functionality precedes these anomalies. The potential crosstalk between adipose tissue and muscle during aging is poorly understood. In this study, it is showed that UCP1 knockout (KO) mice characterized deteriorated brown adipose tissue (BAT) function in aging, yet their glucose homeostasis is sustained and energy expenditure is increased, possibly compensated by improved inguinal adipose tissue (iWAT) and muscle functionality compared to age-matched WT mice. To understand the potential crosstalk, RNA-seq and metabolomic analysis were performed on adipose tissue and muscle in aging mice and revealed that creatine levels are increased both in iWAT and muscle of UCP1 KO mice. Interestingly, molecular analysis and metabolite tracing revealed that creatine biosynthesis is increased in iWAT while creatine uptake is increased in muscle in UCP1 KO mice, suggesting creatine transportation from iWAT to muscle. Importantly, creatine analog β-GPA abolished the differences in muscle functions between aging WT and UCP1 KO mice, while UCP1 inhibitor α-CD improved muscle glycolytic function and glucose metabolism in aging mice. Overall, these results suggested that iWAT and skeletal muscle compensate for declined BAT function during aging via creatine metabolism to sustain metabolic homeostasis.

Keywords:  aging; creatine; glycolytic function; skeletal muscle; thermogenic adipose tissue

DOI:  https://doi.org/10.1002/advs.202411015
Mol Metab. 2024 Nov 19. pii: S2212-8778(24)00197-2. [Epub ahead of print] 102066

AMPK regulates the maintenance and remodelling of the neuromuscular junction.

Sean Y Ng, Andrew I Mikhail, Stephanie R Mattina, Salah A Mohammed, Shahzeb K Khan, Eric M Desjardins, Changhyun Lim, Stuart M Phillips, Gregory R Steinberg, Vladimir Ljubicic.

  The neuromuscular junction (NMJ) is an electrochemical signaling apparatus essential for facilitating muscle contraction and counteracting neurodegenerative processes associated with aging and neuromuscular disorders. Although our understanding of the molecular mechanisms that govern the maintenance and plasticity of the NMJ is limited, recent evidence suggests that AMP-activated protein kinase (AMPK) is an emerging, influential player. Our findings reveal an increased abundance of AMPK transcripts within the NMJ and an age-associated decline in AMPK activity and synapse-specific mitochondrial gene expression. Young mice null for skeletal muscle AMPK displayed a neuromuscular phenotype akin to aged animals. Pharmacological AMPK stimulation facilitated its localization in subsynaptic myonuclei, preceded the induction of several NMJ-related transcripts, and enhanced myotube acetylcholine receptor clustering. Exercise-induced AMPK activation in mouse muscle elicited a broad NMJ-related gene response, consistent with human exercise data. Together, these findings highlight a role for AMPK in the maintenance and remodeling of the NMJ.

Keywords:  Mitochondria; PGC-1α; acetylcholine receptors; aging; exercise

DOI:  https://doi.org/10.1016/j.molmet.2024.102066
Int J Obes (Lond). 2024 Nov 19.

Exploring differential miRNA expression profiles in muscular and visceral adipose tissue of patients with severe obesity.

Carmen Lambert, Paula Morales-Sánchez, Ana Victoria García, Elsa Villa-Fernández, Jèssica Latorre, Miguel García-Villarino, Estrella Olga Turienzo Santos, Lorena Suárez-Gutierrez, Raquel Rodríguez Uría, Sandra Sanz Navarro, Jessica Ares-Blanco, Pedro Pujante, Lourdes María Sanz Álvarez, Edelmiro Menéndez-Torre, María Moreno Gijón, José Manuel Fernandez-Real, Elías Delgado.

BACKGROUND: This study aims to investigate the differential miRNA expression profile between the visceral white adipose tissue and the skeletal muscle of people with obesity undergoing bariatric surgery.
METHODS: Skeletal muscle and visceral adipose tissue samples of 10 controls and 38 people with obesity (50% also with type 2 diabetes) undergoing bariatric surgery were collected. miRNA expression profiles were analyzed using Next-Generation Sequencing and subsequently validated using RT-PCR.
RESULTS: Approximately 69% of miRNAs showed similar expression in both tissues, however, 55 miRNAs were preferentially expressed in visceral adipose tissue and 53 in skeletal muscle. miR-122b-5p was uniquely identified in skeletal muscle, while miR-1-3p and miR-206 were upregulated in skeletal muscle. Conversely, miR-224-5p and miR-335-3p exhibited upregulation in visceral adipose tissue. Notably, distinctions related to the presence of type 2 diabetes were observed solely in the expression of miR-1-3p and miR-206 in visceral adipose tissue.
CONCLUSIONS: This is the first study unveiling distinct miRNA expression profiles in paired samples of visceral adipose tissue and skeletal muscle in humans. The identification of obesity-specific miRNAs in these tissues opens up promising avenues for research into potential biomarkers for obesity diagnosis and treatment.

DOI: https://doi.org/10.1038/s41366-024-01683-4
Biol Res. 2024 Nov 17. 57(1): 86

Overexpression of autophagy enhancer PACER/RUBCNL in neurons accelerates disease in the SOD1G93A ALS mouse model.

Luis Labrador, Leonardo Rodriguez, Sebastián Beltran, Fernanda Hernandez, Laura Gomez, Patricia Ojeda, Cristian Bergmann, Melissa Calegaro-Nassif, Bredford Kerr, Danilo B Medinas, Patricio Manque, Ute Woehlbier.

  Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal paralytic disorder associated with motor neuron death. Mutant superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial ALS, with the accumulation of abnormal wild-type SOD1 species being also observed in postmortem tissue of sporadic ALS cases. Both wild-type and mutated SOD1 are reported to contribute to motoneuron cell death. The autophagic pathway has been shown to be dysregulated in ALS. Recent evidence suggests a dual time-dependent role of autophagy in the progression of the disease. PACER, also called RUBCNL (Rubicon-like), is an enhancer of autophagy and has been found diminished in its levels during ALS pathology in mice and humans. Pacer loss of function disturbs the autophagy process and leads to the accumulation of SOD1 aggregates, as well as sensitizes neurons to death. Therefore, here we investigated if constitutive overexpression of PACER in neurons since early development is beneficial in an in vivo model of ALS. We generated a transgenic mouse model overexpressing human PACER in neurons, which then was crossbred with the mutant SOD1G93A ALS mouse model. Unexpectedly, PACER/SOD1G93A double transgenic mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1G93A mice. The overexpression of PACER in neurons in vivo and in vitro increased the accumulation of SOD1 aggregates, possibly due to impaired autophagy. These results suggest that similar to Pacer loss-of function, Pacer gain-of function is detrimental to autophagy, increases SOD1 aggregation and worsens ALS pathogenesis. In a wider context, our results indicate the requirement to maintain a fine balance of PACER protein levels to sustain proteostasis.

Keywords:  Amyotrophic lateral sclerosis; Autophagy; KIAA0226L; PACER; RUBCNL; SQSTM1; Superoxide dismutase 1; p62

DOI:  https://doi.org/10.1186/s40659-024-00567-1
EMBO Rep. 2024 Nov 19.

Regulating translation in aging: from global to gene-specific mechanisms.

Mathilde Solyga, Amitabha Majumdar, Florence Besse.

  Aging is characterized by a decline in various biological functions that is associated with changes in gene expression programs. Recent transcriptome-wide integrative studies in diverse organisms and tissues have revealed a gradual uncoupling between RNA and protein levels with aging, which highlights the importance of post-transcriptional regulatory processes. Here, we provide an overview of multi-omics analyses that show the progressive uncorrelation of transcriptomes and proteomes during the course of healthy aging. We then describe the molecular changes leading to global downregulation of protein synthesis with age and review recent work dissecting the mechanisms involved in gene-specific translational regulation in complementary model organisms. These mechanisms include the recognition of regulated mRNAs by trans-acting factors such as miRNA and RNA-binding proteins, the condensation of mRNAs into repressive cytoplasmic RNP granules, and the pausing of ribosomes at specific residues. Lastly, we mention future challenges of this emerging field, possible buffering functions as well as potential links with disease.

Keywords:  Aging; Post-transcriptional Regulation; RNA; RNA-Binding Proteins; Tanslation

DOI:  https://doi.org/10.1038/s44319-024-00315-2
Iran J Allergy Asthma Immunol. 2024 Jul 27. 23(4): 393-402

From Mild Cases to Critical Cases of COVID-19: The Role of Genes in Inflammasome and Mitochondrial Dynamics.

Azam Kia, Vahideh Hajhasan, Mona Nadi, Azam Samei, Sadeq Azimzadeh Jamalkandi, Shahram Parvin, Ali Saffaie, Pedram Basirjafar, Jafar Salimian, Azam Samei.

  The coronavirus disease 2019 (CVOID-19) has varied clinical manifestations including mild to severe acute respiratory symptoms. Inflammasome complex and mitochondria play an important role in initiating inflammatory responses and could potentially be affected by this infection. To study the inflammasome and mitochondrial fission and fusion gene expression levels in COVID-19 patients, we designed this experiment. The inflammasome and mitochondrial gene expression profiles were determined by real-time polymerase chain reaction in the peripheral blood of 70 hospitalized CVOID-19 patients with mild to moderate symptoms (HOSP) and 30 ICU patients with severe symptoms (ICU) compared to 20 healthy controls (HC). The results indicated that the expression of the dynamin-related protein-1 was extremely suppressed in HOSP while it came back to the normal range in the ICU group. However, the expression of fission 1 protein had a non-significant increase in HOSP and a decrease in the ICU group. The mitofusin-1 and dominant optic atrophy genes showed high expression levels (10-fold) and (70-fold), respectively, in the HOSP group. However, mitofusin-2 significantly decreased in both groups. Although leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase activating and recruitment domain genes dramatically increased in both groups (10 and 4-fold), other inflammasome genes declined in both groups. Finally, Nuclear factor kappa-light-chain-enhancer of activate d B cells (NF-κB) extremely decreased, and Intreleukine-1 showed high expression in ICU patients (3-fold). CVOID-19 infection suppresses the fission genes and elevates the fusion gene expression in mitochondria, and it can cause activation of the inflammasome via the NLRP3 pathway.

Keywords:  Corona disease 2019 (COVID-19); Inflammasome; Mitochondria

DOI:  https://doi.org/10.18502/ijaai.v23i4.16213
J Autoimmun. 2024 Nov 18. pii: S0896-8411(24)00166-5. [Epub ahead of print]149 103332

Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis.

Antonella Notarnicola, Ceke Hellstrom, Begum Horuluoglu, Elisa Pin, Charlotta Preger, Francesco Bonomi, Boel De Paepe, Jan L De Bleecker, Anneke J Van der Kooi, Marianne De Visser, Sabrina Sacconi, Pedro Machado, Umesh A Badrising, Anke Rietveld, Ger Pruijn, Simon Rothwell, James B Lilleker, Hector Chinoy, Olivier Benveniste, Elisabet Svenungsson, Helena Idborg, Per-Johan Jakobsson, Peter Nilsson, Ingrid E Lundberg.

   BACKGROUND: Autoantibodies are found in up to 80 % of patients with idiopathic inflammatory myopathies (IIM) and are associated with distinct clinical phenotypes. Autoantibodies targeting cytosolic 5'-nucleotidase 1A (anti-NT5C1A) are currently the only known serum biomarker for the subgroup inclusion body myositis (IBM), although detected even in other autoimmune diseases. The aim of the study was to identify new autoimmune targets in IIM.
METHODS: In a first cross-sectional exploratory study, samples from 219 IIM (108 Polymyositis (PM), 80 Dermatomyositis (DM) and 31 IBM) patients, 349 Systemic Lupus Erythematosus (SLE) patients and 306 population controls were screened for IgG reactivity against a panel of 357 proteins using an antigen bead array. All samples were identified in the local biobank of the Rheumatology clinic, Karolinska University Hospital. Positive hits for the IBM subgroup were then validated in an independent larger cohort of 287 patients with IBM followed at nine European rheumatological or neurological centers. IBM serum samples were explored by antigen bead array and results validated by Western blot. As controls, sera from 29 patients with PM and 30 with DM, HLA-matched with the Swedish IBM cohort, were included. Demographics, laboratory, clinical, and muscle biopsy data of the IBM cohort was retrieved.
RESULTS: In the exploratory study, IgG reactivity towards NADH dehydrogenase 1 α subcomplex 11 (NDUFA11), a subunit of the membrane-bound mitochondrial respiratory chain complex I, was discovered with higher frequency in the IBM (9.7 %) than PM (2.8 %) and DM samples (1.3 %), although the difference was not statistically significant. Anti-NDUFA11 IgG was also found in 1.4 % of SLE and 2.0 % of population control samples. In the validation study, anti-NDUFA11 autoantibodies were detected in 10/287 IBM patients (3.5 %), 0/29 p.m. and 0/30 DM patients. Reactivity against NDUFA11 could be confirmed by Western blot. No statistically significant differences were found between patients with and without anti-NDUFA11 antibodies when comparing clinical, laboratory and histological data. However, we observed a trend of higher frequency of distal lower extremity muscle weakness, ragged red fibers and higher CK levels at time of diagnosis in the anti-NDUFA11 positive group. Co-existence of anti-NDUFA11 and anti-NT5C1A antibodies was not observed in any IBM patient.
CONCLUSION: Our results reveal a new autoimmune target in the mitochondrial respiratory chain complex I that might be specifically associated with IBM. This is of particular interest as mitochondrial abnormalities are known histological findings in muscle biopsies of IBM patients.

Keywords:  Autoantibodies; Inclusion body myositis; Mitochondrial respiratory chain complex

DOI:  https://doi.org/10.1016/j.jaut.2024.103332
Cell Metab. 2024 Nov 18. pii: S1550-4131(24)00416-9. [Epub ahead of print]

Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action.

Elise J Needham, Janne R Hingst, Johan D Onslev, Alexis Diaz-Vegas, Magnus R Leandersson, Hannah Huckstep, Jonas M Kristensen, Kohei Kido, Erik A Richter, Kurt Højlund, Benjamin L Parker, Kristen Cooke, Guang Yang, Christian Pehmøller, Sean J Humphrey, David E James, Jørgen F P Wojtaszewski.

  Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (n = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by "priming" a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.

Keywords:  MINDY1; cell signaling; exercise; insulin; insulin resistance; phosphoproteomics; proteomics; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2024.10.020