bims-musmir 2024-09-29 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024‒09‒29
eighteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Unveiling sex differences in skeletal muscle metabolism: the role of HIF1α in normoxia.
Amyotrophic lateral sclerosis as a disease model of sarcopenia.
Tubular Aggregates as a Marker of Aging in Skeletal Muscle.
Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.
Macrophages modulate skeletal muscle wasting and recovery in acute lung injury in mice.
Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle.
Light-phase time-restricted feeding disrupts the muscle clock and insulin sensitivity yet potentially induces muscle fiber remodeling in mice.
Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise.
Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.
Effect of statins on mitochondrial function and contractile force in human skeletal and cardiac muscle.
TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.
Pharmacological and non-pharmacological treatments in amyotrophic lateral sclerosis: an Italian real-world data study.
Effects of intermittent exposure to hypobaric hypoxia and cold on skeletal muscle regeneration: mitochondrial dynamics, protein oxidation and turnover.
The Effects of Maternal Nutrient Restriction during Mid to Late Gestation with Realimentation on Fetal Metabolic Profiles in the Liver, Skeletal Muscle, and Blood in Sheep.
Elevated serum circulating cell-free mitochondrial DNA in amyotrophic lateral sclerosis.
LncRNA OIP5-AS1 regulates ferroptosis and mitochondrial dysfunction-mediated apoptosis in spinal cord injury by targeting the miR-128-3p/Nrf2 axis.
GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia.

J Physiol. 2024 Sep 27.

Unveiling sex differences in skeletal muscle metabolism: the role of HIF1α in normoxia.

Ashlyn Ro, Dorota Kaminska.



Keywords:  HIF1A; mitochondria; normoxia; sex differences; skeletal muscle

DOI:  https://doi.org/10.1113/JP287250
Age Ageing. 2024 Sep 01. pii: afae209. [Epub ahead of print]53(9):

Amyotrophic lateral sclerosis as a disease model of sarcopenia.

Domenico Azzolino, Rachele Piras, Aida Zulueta, Tiziano Lucchi, Christian Lunetta.

  Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.

Keywords:  frailty; motor neuron; muscle; neurodegeneration; nutrition; older people

DOI:  https://doi.org/10.1093/ageing/afae209
Methods Mol Biol. 2024 Sep 25.

Tubular Aggregates as a Marker of Aging in Skeletal Muscle.

Felipe Tadeu Galante Rocha de Vasconcelos, Brandow Willy Souza, Lucas Santos Souza, Mariz Vainzof.

  Tubular aggregates (TA) are skeletal muscle structures that arise from the progressive accumulation of sarcoplasmic reticulum proteins, mainly with aging. Muscle regeneration plays a role in TA formation. TA quantification may aid in the evaluation of muscle aging and genetic muscle degeneration. TA form over time, appears in aging in normal murine muscles. TA reduction in injured conditions may be due to the degeneration-regeneration process in muscles, with loss of damaged muscle fibers and formation of new fibers that do not present protein aggregation. These new regenerated fibers do not improve the function capacity of the aged muscle. Here, we present a methodology for labeling and identifying tubular aggregates in muscle fibers and also the standardization of its quantification.

Keywords:  Aging; Mouse; Muscle regeneration; Muscular dystrophies; Neuromuscular disease; Tubular aggregates

DOI:  https://doi.org/10.1007/7651_2024_567
Geroscience. 2024 Sep 23.

Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.

Robert V Musci, Jordan D Fuqua, Frederick F Peelor, Hoang Van Michelle Nguyen, Arlan Richardson, Solbie Choi, Benjamin F Miller, Jonathan Wanagat.

  Mitochondrial genomic integrity is a key element of physiological processes and health. Changes in the half-life of the mitochondrial genome are implicated in the generation and accumulation of age-induced mitochondrial DNA (mtDNA) mutations, which are implicated in skeletal muscle aging and sarcopenia. There are conflicting data on the half-life of mtDNA, and there is limited information on how aging affects half-life in skeletal muscle. We hypothesized that skeletal muscle mtDNA synthesis rates would decrease with age in both female and male rats concomitant with changes in mtDNA integrity reflected in mtDNA copy number and mutation frequency. We measured mitochondrial genome half-life using stable isotope labeling over a period of 14 days and assessed mtDNA copy number and deletion mutation frequency using digital PCR in the quadriceps muscle of 9-month-old and 26-month-old male and female OKC-HET rats. We found a significant age-related increase in mtDNA half-life, from 132 days at 9 months to 216 days at 26 months of age in OKC-HET quadriceps. Concomitant with the increase in mtDNA half-life, we found an age-related increase in mtDNA deletion mutation frequency in both male and female rats. Notably, 26-month-old female rats had a lower mutation frequency than male rats, and there were no changes in mtDNA copy number with sex, age, or mitochondrial genotype. These data reveal several key findings: (1) mtDNA turnover in rat skeletal muscle decreases with age, (2) mtDNA half-lives in skeletal muscle are approximately an order of magnitude longer than what is reported for other tissues, and (3) muscle mtDNA turnover differs significantly from the turnover of other mitochondrial macromolecules including components of the mitochondrial nucleoid. These findings provide insight into the factors driving age-induced mtDNA mutation accumulation, which contribute to losses of mitochondrial genomic integrity and may play a role in skeletal muscle dysfunction.

Keywords:  Aging; Deuterium oxide; Mitochondrial DNA; Mutation; Rats; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-024-01344-4
Physiol Rep. 2024 Sep;12(18): e70052

Macrophages modulate skeletal muscle wasting and recovery in acute lung injury in mice.

Jennifer T W Krall, Lanazha Belfield, Claire Strysick, Chun Liu, Lina Purcell, Renee Stapleton, Michael Toth, Matthew Poynter, Xuewei Zhu, Kevin Gibbs, D Clark Files.

  Skeletal muscle dysfunction in critical illnesses leaves survivors weak and functionally impaired. Macrophages infiltrate muscles; however, their functional role is unclear. We aim to examine muscle leukocyte composition and the effect of macrophages on muscle mass and function in the murine acute lung injury (ALI)-associated skeletal muscle wasting model. We performed flow cytometry of hindlimb muscle to identify myeloid cells pre-injury and time points up to 29 days after intratracheal lipopolysaccharide ALI. We evaluated muscle force and morphometrics after systemic and intramuscular clodronate-induced macrophage depletions between peak lung injury and recovery (day 5-6) versus vehicle control. Our results show muscle leukocytes changed over ALI course with day 3 neutrophil infiltration (130.5 ± 95.6cells/mg control to 236.3 ± 70.6cells/mg day 3) and increased day 10 monocyte abundance (5.0 ± 3.4%CD45+CD11b+ day 3 to 14.0 ± 2.6%CD45+CD11b+ day 10, p = 0.005). Although macrophage count did not significantly change, pro-inflammatory (27.0 ± 7.2% day 3 to 7.2 ± 3.8% day 10, p = 0.02) and anti-inflammatory (30.5 ± 11.1% day 3 to 52.7 ± 9.7% day 10, p = 0.09) surface marker expression changed over the course of ALI. Macrophage depletion following peak lung injury increased muscle mass and force generation. These data suggest muscle macrophages beyond peak lung injury limit or delay muscle recovery. Targeting macrophages could augment muscle recovery following lung injury.

Keywords:  acute lung injury; acute respiratory distress syndrome; intensive care unit acquired weakness; macrophage; skeletal muscle wasting

DOI:  https://doi.org/10.14814/phy2.70052
Curr Osteoporos Rep. 2024 Sep 26.

Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle.

John Gostage, Paul Kostenuik, Katarzyna Goljanek-Whysall, Ilaria Bellantuono, Eugene McCloskey, Nicolas Bonnet.

  PURPOSE OF REVIEW: This review aims to consolidate recent observations regarding extra-osseous roles of the RANK-RANKL-OPG axis, primarily within skeletal muscle.RECENT FINDINGS: Preclinical efforts to decipher a common signalling pathway that links the synchronous decline in bone and muscle health in ageing and disease disclosed a potential role of the RANK-RANKL-OPG axis in skeletal muscle. Evidence suggests RANKL inhibition benefits skeletal muscle function, mass, fibre-type switching, calcium homeostasis and reduces fall incidence. However, there still exists ambiguity regarding the exact mechanistic actions and subsequent functional improvements. Other potential RANK-RANKL-OPG extra-osseous roles include regulation of neural-inflammation and glucose metabolism. Growing evidence suggests the RANK-RANKL-OPG axis may play a regulatory role in extra-osseous tissues, especially in skeletal muscle. Targeting RANKL may be a novel therapy in ameliorating loss of muscle mass and function. More research is warranted to determine the causality of the RANK-RANKL-OPG axis in extra-osseous tissues, especially those affected by aging.

Keywords:  Denosumab; Extra-osseous; NF-κB signalling; Osteoprotegerin; RANK-RANKL-OPG axis; Skeletal muscle

DOI:  https://doi.org/10.1007/s11914-024-00890-2
Heliyon. 2024 Sep 30. 10(18): e37475

Light-phase time-restricted feeding disrupts the muscle clock and insulin sensitivity yet potentially induces muscle fiber remodeling in mice.

Zhou Ye, Kai Huang, Xueqin Dai, Dandan Gao, Yue Gu, Jun Qian, Feng Zhang, Qiaocheng Zhai.

  Skeletal muscle plays a critical role in regulating systemic metabolic homeostasis. It has been demonstrated that time-restricted feeding (TRF) during the rest phase can desynchronize the suprachiasmatic nucleus (SCN) and peripheral clocks, thereby increasing the risk of metabolic diseases. However, the impact of dietary timing on the muscle clock and health remains poorly understood. Here, through the analysis of cycling genes and differentially expressed genes in the skeletal muscle transcriptome, we identified disruptions in muscle diurnal rhythms by 2 weeks of light-phase TRF. Furthermore, compared with ad libitum (AL) feeding mice, 2 weeks of light-phase TRF was found to induce insulin resistance, muscle fiber type remodeling, and changes in the expression of muscle growth-related genes, while both light-phase and dark-phase TRF having a limited impact on bone quality relative to AL mice. In summary, our research reveals that the disruption of the skeletal muscle clock may contribute to the abnormal metabolic phenotype resulting from feeding restricted to the inactive period. Additionally, our study provides a comprehensive omics atlas of the diurnal rhythms in skeletal muscle regulated by dietary timing.

Keywords:  Bone mass; Circadian clock; Muscle fiber remodeling; Skeletal muscle; Time-restricted feeding

DOI:  https://doi.org/10.1016/j.heliyon.2024.e37475
JCI Insight. 2024 Sep 24. pii: e182589. [Epub ahead of print]

Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise.

Benjamin I Burke, Ahmed Ismaeel, Douglas E Long, Lauren A Depa, Peyton T Coburn, Jensen Goh, Tolulope P Saliu, Bonnie J Walton, Ivan J Vechetti, Bailey D Peck, Taylor R Valentino, C Brooks Mobley, Hasiyet Memetimin, Dandan Wang, Brian S Finlin, Philip A Kern, Charlotte A Peterson, John J McCarthy, Yuan Wen.

  Extracellular vesicles (EVs) have emerged as important mediators of inter-tissue signaling and exercise adaptations. In this human study (n = 32), we provide evidence that muscle-specific microRNA-1 (miR-1) was transferred to adipose tissue via EVs following an acute bout of resistance exercise. Using a multi-model machine learning automation tool, we discovered muscle primary miR-1 transcript and CD63+ EV count in circulation as top explanatory features for changes in adipose miR-1 levels in response to resistance exercise. RNA-sequencing (RNA-seq) and in-silico prediction of miR-1 target genes identified caveolin 2 (CAV2) and tripartite motif containing 6 (TRIM6) as miR-1 target genes downregulated in the adipose tissue of a subset of participants with the highest increases in miR-1 levels following resistance exercise (n = 6). Overexpression of miR-1 in differentiated human adipocyte-derived stem cells downregulated these miR-1 targets and enhanced catecholamine-induced lipolysis. These data identify a potential EV-mediated mechanism by which skeletal muscle communicates to adipose tissue and modulates lipolysis via miR-1.

Keywords:  Adipose tissue; Metabolism; Muscle biology; Skeletal muscle; Transport

DOI:  https://doi.org/10.1172/jci.insight.182589
Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00675-0. [Epub ahead of print]

Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.

N Moradi, V C Sanfrancesco, S Champsi, D A Hood.

Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.09.028
Autophagy. 2024 Oct;20(10): 2164-2185

Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.

Hortense de Calbiac, Solène Renault, Grégoire Haouy, Vincent Jung, Kevin Roger, Qihui Zhou, Maria-Letizia Campanari, Loïc Chentout, Doris Lou Demy, Anca Marian, Nicolas Goudin, Dieter Edbauer, Chiara Guerrera, Sorana Ciura, Edor Kabashi.

  The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.

Keywords:  Amyotrophic lateral sclerosis; apoptosis; mitochondria; motor neuron; neurodegeneration; poly-GP

DOI:  https://doi.org/10.1080/15548627.2024.2358736
Biomed Pharmacother. 2024 Sep 25. pii: S0753-3322(24)01378-7. [Epub ahead of print]180 117492

Effect of statins on mitochondrial function and contractile force in human skeletal and cardiac muscle.

Tim Somers, Sailay Siddiqi, Margit C M Janssen, Wim J Morshuis, Renee G C Maas, Jan W Buikema, Petra H H van den Broek, Tom J J Schirris, Frans G M Russel.

  OBJECTIVES AND BACKGROUND: The success of statin therapy in reducing cardiovascular morbidity and mortality is contrasted by the skeletal muscle complaints, which often leads to nonadherence. Previous studies have shown that inhibition of mitochondrial function plays a key role in statin intolerance. Recently, it was found that statins may also influence energy metabolism in cardiomyocytes. This study assessed the effects of statin use on cardiac muscle ex vivo from patients using atorvastatin, rosuvastatin, simvastatin or pravastatin and controls.METHODS: Cardiac tissue and skeletal muscle tissue were harvested during open heart surgery after patients provided written informed consent. Patients included were undergoing cardiac surgery and either taking statins (atorvastatin, rosuvastatin, simvastatin or pravastatin) or without statin therapy (controls). Contractile behaviour of cardiac auricles was tested in an ex vivo set-up and cellular respiration of both cardiac and skeletal muscle tissue samples was measured using an Oxygraph-2k. Finally, statin acid and lactone concentrations were quantified in cardiac and skeletal homogenates by LC-MS/MS.
RESULTS: Fatty acid oxidation and mitochondrial complex I and II activity were reduced in cardiac muscle, while contractile function remained unaffected. Inhibition of mitochondrial complex III by statins, as previously described, was confirmed in skeletal muscle when compared to control samples, but not observed in cardiac tissue. Statin concentrations determined in skeletal muscle tissue and cardiac muscle tissue were comparable.
CONCLUSIONS: Statins reduce skeletal and cardiac muscle cell respiration without significantly affecting cardiac contractility.

Keywords:  Cardiac muscle; Cellular respiration; Contractile force; Heart auricle; Skeletal muscle

DOI:  https://doi.org/10.1016/j.biopha.2024.117492
Acta Neuropathol. 2024 Sep 21. 148(1): 45

TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.

Pascual Torres, Santiago Rico-Rios, Miriam Ceron-Codorniu, Marta Santacreu-Vilaseca, David Seoane-Miraz, Yahya Jad, Victòria Ayala, Guillermo Mariño, Maria Beltran, Maria P Miralles, Pol Andrés-Benito, Joaquin Fernandez-Irigoyen, Enrique Santamaria, Carlos López-Otín, Rosa M Soler, Monica Povedano, Isidro Ferrer, Reinald Pamplona, Matthew J A Wood, Miguel A Varela, Manuel Portero-Otin.

  Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b-/- mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.

Keywords:  ALS; Antisense oligonucleotides; Autophagy; Digital PCR; Post-translational modification

DOI:  https://doi.org/10.1007/s00401-024-02780-4
Eur J Neurol. 2024 Sep 19. e16470

Pharmacological and non-pharmacological treatments in amyotrophic lateral sclerosis: an Italian real-world data study.

CAESAR study group

  BACKGROUND AND PURPOSE: The purpose was to describe the use patterns of pharmacological and non-pharmacological therapies and investigate potential determinants of riluzole use in patients newly diagnosed with amyotrophic lateral sclerosis (ALS) in three Italian regions.METHODS: Amyotrophic lateral sclerosis patients were selected from administrative healthcare databases of Latium, Tuscany and Umbria from 1 January 2014 to 31 December 2019 based on hospital- and disease-specific co-payment exemption data. The first trace of ALS was considered the index date. Incident ALS cases were those without a trace of ALS during the 3-year look back. Patients were described in terms of demographics, clinical characteristics and drug use at baseline, and were classified into four categories based on riluzole use in the 2 years before and 1 year after the index date: prevalent, incident, former users and non-users. Use of symptomatic pharmacological and non-pharmacological therapies was described across these categories during 12 months after the index date. Determinants of riluzole use were also investigated.
RESULTS AND CONCLUSIONS: A total of 1636 ALS incident subjects were detected in the three regions, mainly aged 65-74 years. Patients were generally fragile with a high prevalence of comorbidities at baseline. Riluzole was used by 27.4% of the overall study cohort at baseline and steeply increased in the first year after the index date differently between regions (Latium 61.2%, Tuscany 85.0%, Umbria 76.5%), with about half of the subjects being incident users. In the 12 months after the index date, also symptomatic therapies increased, in riluzole users and non-users. Determinants analysis showed that higher patient severity and complexity were associated with a lower likelihood of being treated with riluzole.

Keywords:  amyotrophic lateral sclerosis; determinants of use; pharmaco‐utilization; riluzole

DOI:  https://doi.org/10.1111/ene.16470
Free Radic Biol Med. 2024 Sep 21. pii: S0891-5849(24)00679-8. [Epub ahead of print]

Effects of intermittent exposure to hypobaric hypoxia and cold on skeletal muscle regeneration: mitochondrial dynamics, protein oxidation and turnover.

Sergio Sánchez-Nuño, Garoa Santocildes, Josep Rebull, Raquel G Bardallo, Montserrat Girabent, Ginés Viscor, Teresa Carbonell, Joan Ramon Torrella.

  Muscle injuries and the subsequent regeneration events compromise muscle homeostasis at morphological, functional and molecular levels. Among the molecular alterations, those derived from the mitochondrial function are especially relevant. We analysed the mitochondrial dynamics, the redox balance, the protein oxidation and the main protein repairing mechanisms after 9 days of injury in the rat gastrocnemius muscle. During the recovery rats were exposed to intermittent cold exposure (ICE), intermittent hypobaric hypoxia (IHH), and both simultaneous combined stimuli. Non-injured contralateral legs were also analysed to evaluate the specific effects of the three environmental exposures. Our results showed that ICE enhanced mitochondrial adaptation by improving the electron transport chain efficiency during muscle recovery, decreased the expression of regulatory subunit of proteasome and accumulated oxidised proteins. Exposure to IHH did not show mitochondrial compensation or increased protein turnover mechanisms; however, no accumulation of oxidized proteins was observed. Both ICE and IHH, when applied separately, elicited an increased expression of eNOS, which could have played an important role in accelerating muscle recovery. The combined effect of ICE and IHH led to a complex response that could potentially impede optimal mitochondrial function and enhanced the accumulation of protein oxidation. These findings underscore the nuanced role of environmental stressors in the muscle healing process and their implications for optimizing recovery strategies.

Keywords:  Electron transport chain; Intermittent cold exposure; Intermittent hypobaric hypoxia; protein oxidation; redox

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.032
Metabolites. 2024 Aug 23. pii: 465. [Epub ahead of print]14(9):

The Effects of Maternal Nutrient Restriction during Mid to Late Gestation with Realimentation on Fetal Metabolic Profiles in the Liver, Skeletal Muscle, and Blood in Sheep.

Brandon I Smith, Manuel A Vásquez-Hidalgo, Xiaomeng Li, Kimberly A Vonnahme, Anna T Grazul-Bilska, Kendall C Swanson, Timothy E Moore, Sarah A Reed, Kristen E Govoni.

  Poor maternal nutrition during gestation negatively affects offspring growth and metabolism. To evaluate the impact of maternal nutrient restriction and realimentation on metabolism in the fetal liver, skeletal muscle, and circulation, on day 50 of gestation, ewes (n = 48) pregnant with singletons were fed 100% (CON) or 60% (RES) of requirements until day 90 of gestation, when a subset of ewes (n = 7/treatment) were euthanized, and fetal samples were collected. The remaining ewes were maintained on a current diet (CON-CON, n = 6; RES-RES, n = 7) or switched to an alternative diet (CON-RES, RES-CON; n = 7/treatment). On day 130 of gestation, the remaining ewes were euthanized, and fetal samples were collected. Fetal liver, longissimus dorsi (LD), and blood metabolites were analyzed using LC-MS/MS, and pathway enrichment analysis was conducted using MetaboAnalyst. Then, 600, 518, and 524 metabolites were identified in the liver, LD, and blood, respectively, including 345 metabolites that were present in all three. Nutrient restriction was associated with changes in amino acid, carbohydrate, lipid, and transulfuration/methionine metabolic pathways, some of which were alleviated by realimentation. Fetal age also affected metabolite abundance. The differential abundance of metabolites involved in amino acid, methionine, betaine, and bile acid metabolism could impact fetal epigenetic regulation, protein synthesis, lipid metabolism, and signaling associated with glucose and lipid metabolism.

Keywords:  circulation; developmental programming; liver; maternal nutrition; metabolism; muscle

DOI:  https://doi.org/10.3390/metabo14090465
Eur J Neurol. 2024 Sep 26. e16493

Elevated serum circulating cell-free mitochondrial DNA in amyotrophic lateral sclerosis.

Jieyu Li, Chao Gao, Qingqing Wang, Jing Liu, Zhiying Xie, Yawen Zhao, Meng Yu, Yiming Zheng, He Lv, Wei Zhang, Yun Yuan, Lingchao Meng, Jianwen Deng, Zhaoxia Wang.

  BACKGROUND AND PURPOSE: The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients.METHODS: The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n = 62) and age-matched healthy controls (n = 46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed.
RESULTS: Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1 × 105 mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p < 0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (ΔFS; rs = -0.26, p = 0.044), but not the ALSFRS-R score (rs = 0.06, p = 0.625). Importantly, the correlation between ccf-mtDNA and ΔFS was more pronounced in the SOD1 mutation group (rs = -0.62, p = 0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r s= 0.41, p = 0.038).
CONCLUSION: Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.

Keywords:  amyotrophic lateral sclerosis; circulating cell‐free mitochondrial DNA; disease progression; inflammation

DOI:  https://doi.org/10.1111/ene.16493
Heliyon. 2024 Sep 30. 10(18): e37704

LncRNA OIP5-AS1 regulates ferroptosis and mitochondrial dysfunction-mediated apoptosis in spinal cord injury by targeting the miR-128-3p/Nrf2 axis.

Zhensong Jiang, Weimin Zhang, Jianru Zhang.

  Background: Ferroptosis is an important way of neuronal cell death in acute phase and participates in the inflammatory cascade after spinal cord injury (SCI). It is reported that microRNA (miRNA) and long non-coding RNA (lncRNA) are key mediators in the regulation of ferroptosis. This study will explore the inhibitory effect of LncRNA OIP5-AS1 on ferroptosis and mitochondrial dysfunction-mediated apoptosis in SCI.Methods: The ferric ammonium citrate (FAC)-induced cell model and the SCI rat model were established. The expression of LncRNA OIP5-AS1, miR-128-3p and Nrf2 were transfected to evaluated the effect on the viability and apoptosis of FAC-induced cell. The interaction between LncRNA OIP5-AS1 and miR-128-3p or miR-128-3p and Nrf2 were analyzed. In addition, expressions of markers related to ferroptosis and mitochondrial dysfunction were analyzed in vitro and in vivo. Histopathologic slide staining was used to analyze spinal cord injury in vivo.
Results: LncRNA OIP5-AS1 expression was abnormally down-regulated in FAC-induced SCI cell model and SCI rats. The LncRNA OIP5-AS1 deficiency induced decreased Nrf2 level by less sponging miR-128-3p, thus, aggravating spinal cord injury and inducing more apoptosis, ferroptosis and mitochondrial dysfunction in neural stem cells with SCI. However, overexpression of LncRNA OIP5-AS1 inhibited apoptosis, ferroptosis and mitochondrial dysfunction, thus effectively ameliorating spinal cord injury.
Conclusion: This finding demonstrates that LncRNA OIP5-AS1 overexpression could enhance the recovery of spinal cord injury by regulating the miR-128-3p/Nrf2 axis.

Keywords:  Ferroptosis; LncRNA OIP5-AS1; Mitochondrial dysfunction; Nrf2; Spinal cord injury; miR-128-3p

DOI:  https://doi.org/10.1016/j.heliyon.2024.e37704
Signal Transduct Target Ther. 2024 Sep 26. 9(1): 253

GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia.

Xu Chen, Qingnan Wu, Wei Gong, Shaolong Ju, Jiawen Fan, Xiaohan Gao, Xingyang Liu, Xiao Lei, Siqi Liu, Xiangdong Ming, Qianyu Wang, Ming Fu, Yongmei Song, Yan Wang, Qimin Zhan.

Cachexia, which affects 50-80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75-ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.

DOI: https://doi.org/10.1038/s41392-024-01950-w