bims-musmir 2024-12-08 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–12–08
eight papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Skeletal muscle proteome differs between young APOE3 and APOE4 targeted replacement mice in a sex-dependent manner.
Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism.
Circadian Dysfunction in the Skeletal Muscle Impairs Limb Perfusion and Muscle Regeneration in Peripheral Artery Disease.
Islet-derived exosomal miR-204 accelerates insulin resistance in skeletal muscle by suppressing sirtuin 1: An in vivo study in a mouse model of high-fat diet-induced obesity.
Diversity in Chemotherapy-Induced Cachexia.
OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.
Research progress on the correlation between estrogen and estrogen receptor on postmenopausal sarcopenia.
Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study.

Front Aging Neurosci. 2024 ;16 1486762

Skeletal muscle proteome differs between young APOE3 and APOE4 targeted replacement mice in a sex-dependent manner.

Chelsea N Johnson, Colton R Lysaker, Colin S McCoin, Mara R Evans, John P Thyfault, Heather M Wilkins, Jill K Morris, Paige C Geiger.

   Introduction: Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), yet it's unclear how this allele mediates risk. APOE4 carriers experience reduced mobility and faster decline in muscle strength, suggesting skeletal muscle involvement. Mitochondria are critical for muscle function and although we have reported defects in muscle mitochondrial respiration during early cognitive decline, APOE4-mediated effects on muscle mitochondria are unknown.
Methods: Here, we sought to determine the impact of APOE4 on skeletal muscle bioenergetics using young, male and female APOE3 (control) and APOE4 targeted replacement mice (n = 8 per genotype/sex combination). We examined the proteome, mitochondrial respiration, fiber size, and fiber-type distribution in skeletal muscle.
Results: We found that APOE4 alters mitochondrial pathway expression in young mouse muscle in a sex-dependent manner without affecting respiration and fiber size or composition relative to APOE3. In both sexes, the expression of mitochondrial pathways involved in electron transport, ATP synthesis, and heat production by uncoupling proteins and mitochondrial dysfunction significantly differed between APOE4 and APOE3 muscle. For pathways with predicted direction of activation, electron transport and oxidative phosphorylation were upregulated while mitochondrial dysfunction and sirtuin signaling were downregulated in female APOE4 vs. APOE3 muscle. In males, sulfur amino acid metabolism was upregulated in APOE4 vs. APOE3 muscle.
Discussion: This work highlights early involvement of skeletal muscle in a mouse model of APOE4-linked AD, which may contribute to AD pathogenesis or serve as a biomarker for brain health.

Keywords:  APOE4; Alzheimer's disease; mice; mitochondria; proteomics; skeletal muscle

DOI:  https://doi.org/10.3389/fnagi.2024.1486762
BMC Med. 2024 12 02. 22(1): 572

Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism.

Charlotte Ling, Magdalena Vavakova, Bilal Ahmad Mir, Johanna Säll, Alexander Perfilyev, Melina Martin, Per-Anders Jansson, Cajsa Davegårdh, Olof Asplund, Ola Hansson, Allan Vaag, Emma Nilsson.

   BACKGROUND: A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.
METHODS: By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.
RESULTS: Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D. Differential expression levels of one or more predicted target relevant miRNA(s) were identified for approximately 35% of the dysregulated GSEA pathways. These include miRNAs with a significant overrepresentation of targets involved in GLUT4 translocation (miR-4643 and miR-548z), signaling by receptor tyrosine kinases pathways (miR-607), and muscle contraction (miR-4658). Acquired DNA methylation changes in skeletal muscle were quantitatively small in twins with T2D compared with the co-twins without T2D. Key methylation and expression results were validated in muscle, myotubes, and/or myoblasts from unrelated subjects with T2D and controls. Finally, mimicking T2D-associated changes by overexpressing miR-548 and miR-607 in cultured myotubes decreased expression of target genes, GLUT4 and FGFR4, respectively, and impaired insulin-stimulated phosphorylation of Akt (Ser473) and TBC1D4.
CONCLUSIONS: Together, we show that T2D is associated with non- and epigenetically determined differential transcriptional regulation of pathways regulating skeletal muscle metabolism and contraction.

Keywords:  DNA methylation; Discordant monozygotic twins; Epigenetics; Gene expression; MicroRNA (miRNA); Skeletal muscle; Type 2 diabetes (T2D)

DOI:  https://doi.org/10.1186/s12916-024-03789-y
Arterioscler Thromb Vasc Biol. 2024 Dec 05.

Circadian Dysfunction in the Skeletal Muscle Impairs Limb Perfusion and Muscle Regeneration in Peripheral Artery Disease.

Pei Zhu, Calvin L Chao, Adam W T Steffeck, Caitlyn Dang, Noah X Hamlish, Eric M Pfrender, Bin Jiang, Clara B Peek.

   BACKGROUND: Peripheral artery disease (PAD), caused by atherosclerosis, leads to limb ischemia, muscle damage, and impaired mobility in the lower extremities. Recent studies suggest that circadian rhythm disruptions can hinder vascular repair during ischemia, but the specific tissues involved and the impact on muscle health remain unclear. This study investigates the role of the skeletal muscle circadian clock in muscle adaptation to ischemic stress using a surgical mouse model of hindlimb ischemia.
METHODS: We performed secondary analysis of publicly available RNA-sequencing data sets derived from patients with PAD to identify the differential expression of circadian-related genes in endothelial cells and ischemic limb skeletal muscles. We used mice with specific genetic loss of the circadian clock activator, BMAL1 (brain and muscle ARNT-like 1), in adult skeletal muscle tissues (Bmal1muscle). Bmal1muscle mice and controls underwent femoral artery ligation surgery to induce hindlimb ischemia. Laser Doppler imaging was used to assess limb perfusion at various time points after the surgery. Muscle tissues were analyzed with RNA sequencing and histological examination to investigate PAD-related muscle pathologies. Additionally, we studied the role of BMAL1 in muscle fiber adaptation to hypoxia using RNA and assay for transposase-accessible chromatin with sequencing analyses in primary myotube culture model.
RESULTS: Disrupted expression of circadian rhythm-related genes was observed in existing RNA-sequencing data sets from endothelial cells and ischemic limb skeletal muscles derived from patients with PAD. Genetic loss of Bmal1 specifically in adult mouse skeletal muscle tissues delayed reperfusion recovery following induction of hindlimb ischemia. Histological examination of muscle tissues showed reduced regenerated myofiber number and a decreased proportion of type IIB fast-twitch myofibers in Bmal1muscle mouse muscles in the ischemic limbs but not in their contralateral nonischemic limbs. Transcriptomic analysis revealed abrogated metabolic, angiogenic, and myogenic pathways relevant to hypoxia adaptation in Bmal1muscle mouse muscles. These changes were corroborated in Bmal1-deficient cultured primary myotubes cultured under hypoxic conditions.
CONCLUSIONS: Circadian clock in skeletal muscle is crucial for the muscle's response to hypoxia during hindlimb ischemia. Targeting the muscle circadian clock may have therapeutic potential for enhancing muscle response to reduced blood flow and promoting recovery in conditions such as PAD.

Keywords:  atherosclerosis; femoral artery; ischemia; perfusion; reperfusion

DOI:  https://doi.org/10.1161/ATVBAHA.124.321772
Diabetes Obes Metab. 2024 Dec 05.

Islet-derived exosomal miR-204 accelerates insulin resistance in skeletal muscle by suppressing sirtuin 1: An in vivo study in a mouse model of high-fat diet-induced obesity.

Xuehan Yang, Hao Han, Sushan Wang, Fei Teng, Xiaoyan Lv, Meishuang Zhang, Ying Zhang, Wei Li, Ming Zhang, Li Chen, Siwei Zhang.

   AIMS: The interaction between pancreatic islets and skeletal muscle plays a pivotal role in the development of insulin resistance. The present study aimed to elucidate the impact of non-hormonal molecules from islets on the insulin sensitivity of skeletal muscle cells.
MATERIALS AND METHODS: We developed a mouse model of obesity through a high-fat diet, assessing glucose tolerance and conducting miRNA sequencing on skeletal muscle samples. An in vitro model was established by treating cells with palmitic acid, and exosomes in the supernatant were characterized using scanning electron microscopy and CD63 expression analysis. Intracellular miR-204-5p levels were quantified by RT-PCR.
RESULTS: Our in vivo model demonstrated a robust correlation between miR-204-5p level alterations and obesity-induced insulin resistance. Elevated fatty acid levels were observed to increase miR-204-5p in both skeletal muscle and islets. In cellular studies, palmitic acid increased miR-204-5p in MIN-6 islet β-cells but not in C2C12 skeletal muscle cells. Exosomes containing miR-204-5p, secreted by palmitic acid-treated MIN6 cells, were identified through morphological examination, immunoblotting for the exosomal marker CD63, and intraexosomal miR-204-5p level measurement. C2C12 cells were shown to uptake islet-derived miR-204-5p exosomes, as evidenced by the uptake of Exo-Red labeled exosomes. TargetScan analysis identified a highly conserved binding site for miR-204-5p in the 3' UTR of Sirt mRNA. Functional studies indicated that miR-204-5p overexpression reduced glucose consumption and uptake in C2C12 cells, decreased Sirt expression, and impaired insulin signaling, as evidenced by reduced Akt phosphorylation and membrane Glut4 levels.
CONCLUSIONS: Our findings reveal that miR-204-5p contributes to the development of insulin resistance in obesity and acts as a signaling molecule in the crosstalk between pancreatic islets and skeletal muscle.

Keywords:  exosomes; insulin resistance; miR‐204‐5p; sirtuin 1; skeletal muscle

DOI:  https://doi.org/10.1111/dom.16102
Am J Physiol Cell Physiol. 2024 Dec 05.

Diversity in Chemotherapy-Induced Cachexia.

Leah J Novinger, Natalia M Weinzierl, Andrea Bonetto.

  Preclinical and clinical studies suggest that chronic administration of cytotoxic drugs (e.g., chemotherapy) may contribute to the occurrence of skeletal muscle wasting and weakness/fatigue (i.e., cachexia). Doxorubicin, folfiri, and cisplatin are known to promote cachexia by triggering common alterations such as skeletal muscle atrophy, protein breakdown, and mitochondrial dysfunction, whereas each also possesses distinguishing features in terms of the activated molecular pathways. Similarly, commonalities exist between different cancer types including the development of muscle wasting early in treatment that can persist for years. The impact of treatment for gastrointestinal, head and neck and non-small cell lung cancers on the development of cachexia and survival outcomes is well documented. However, a disconnect occurs between preclinical studies on cachexia, which are often performed on younger mice, and clinical studies on cachexia, which are focused on patients over 60 years old. Yet, several preclinical studies have examined the impact of age on chemotherapy-induced cachexia. Finally, sex differences have been identified in both preclinical and clinical studies focused on the onset of cachexia consequential to chemotherapy administration and raise the question of whether treatments for this condition should be based on sex specificities. In conclusion, while cancer cachexia has been widely studied for its impact on patients affected by various malignancies, the effects of chemotherapy on the development of cachexia are less explored. Here, we examine diversity in chemotherapy-induced cachexia with respect to specific types of chemotherapy regimens and cancer, as well as differences based on age and sex.

Keywords:  Chemotherapy; cancer cachexia; elderly; sexual dimorphism; skeletal muscle index

DOI:  https://doi.org/10.1152/ajpcell.00773.2024
Cell Death Dis. 2024 Nov 30. 15(11): 870

OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.

J Macuada, I Molina-Riquelme, G Vidal, N Pérez-Bravo, C Vásquez-Trincado, G Aedo, D Lagos, P Yu-Wai-Man, R Horvath, T J Rudge, B Cartes-Saavedra, V Eisner.

Optic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on nucleoid distribution using high-resolution confocal microscopy. We applied a novel model incorporating the mitochondrial context, separating nucleoid distribution into the array in the mitochondrial population and intramitochondrial longitudinal distribution. Opa1-null cells showed decreased mtDNA levels and nucleoid abundance. Also, loss of Opa1 led to an altered distribution of nucleoids in the mitochondrial population, loss of cristae periodicity, and altered nucleoids to cristae proximity partly rescued by OPA1 isoform 1. Overexpression of WT OPA1 or ADOA-causing mutants c.870+5 G > A or c.2713 C > T in WT cells, showed perturbed nucleoid array in the mitochondria population associated with cristae disorganization, which was partly reproduced in Skeletal muscle-derived fibroblasts from ADOA patients harboring the same mutants. Opa1-null and cells overexpressing ADOA mutants accumulated mitochondria without nucleoids. Interestingly, intramitochondrial nucleoid distribution was only altered in Opa1-null cells. Altogether, our results highlight the relevance of OPA1 in nucleoid distribution in the mitochondrial landscape and at a single-organelle level and shed light on new components of ADOA etiology.

DOI: https://doi.org/10.1038/s41419-024-07165-9
Front Endocrinol (Lausanne). 2024 ;15 1494972

Research progress on the correlation between estrogen and estrogen receptor on postmenopausal sarcopenia.

Chengmei Zhang, Xin Feng, Xue Zhang, Yu Chen, Juan Kong, Yan Lou.

  Estrogen is a necessary sex steroid and potent neuroprotective hormone. It plays a multifaceted role beyond the reproductive system, extending its influence to the brain, skeletal muscle, and other organs. Estrogen's role in cognition, mood, autonomic regulation, and neuroprotection involves interactions with neurotransmitters, neuromodulators in a distributed manner. Notably, the impact of estrogen on mitochondrial metabolism in skeletal muscle is particularly significant due to a unique modulated bioenergetic profiles, synaptic plasticity, and neuronal health. The deficiency of estrogen in menopause has been linked to changes in brain structure, connectivity, energy metabolism. Therewith, these are crucial factors in cognitive function and the risk of Alzheimer's diseases. Besides, it leads to endocrine and metabolic dysfunction, resulting in osteoporosis, metabolic syndrome, and a tendency toward decreased muscle mass and strength. Estrogen's influence on mitochondrial function is particularly relevant to aging, as it affects the production of ATP and the overall metabolic health of the brain. Estrogen decline in women skeletal muscle mass is usually related to sarcopenia, a prevalent disease observed in vulnerable elderly individuals. Therefore, estrogen is considered to play a crucial role in skeletal muscle homeostasis and motor ability, although the exact mechanism remains unclear. This paper reviews the literature on the impact of estrogen on postmenopausal skeletal muscle diseases and the underlying molecular mechanisms, especially in terms of mitochondrial metabolism. In summary, estrogen plays an important role in the health of skeletal muscle in postmenopausal women, and its impact on mitochondrial function and homeostasis offers potential targets for the development of new strategies to treat sarcopenia.

Keywords:  estrogen; estrogen receptor; postmenopausal sarcopenia; sex steroid hormone; skeletal muscle

DOI:  https://doi.org/10.3389/fendo.2024.1494972
J Cachexia Sarcopenia Muscle. 2024 Dec 02.

Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study.

Stefano Donega, Nirad Banskota, Esha Gupta, Marta Gonzalez-Freire, Ann Zenobia Moore, Ceereena Ubaida-Mohien, Rachel Munk, Linda Zukley, Yulan Piao, Chris Bergeron, Jan Bergeron, Arsun Bektas, Marta Zampino, Carole Stagg, Fred Indig, Lisa M Hartnell, Mary Kaileh, Kenneth Fishbein, Richard G Spencer, Myriam Gorospe, Supriyo De, Josephine M Egan, Ranjan Sen, Luigi Ferrucci.

   BACKGROUND: Physical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals.
METHODS: Using RNA sequencing of vastus lateralis muscle biopsies from 82 GESTALT participants (52 males, aged 22-89 years), we explored gene and splicing variant expression profiles associated with self-reported physical activity, peak oxygen consumption (VO2 peak), muscle oxidative capacity (kPCr) and mitochondrial respiration (Mit-O2 flux). The effect of aging on gene expression was examined in participants with low and high VO2 peak.
RESULTS: The four measures of energetics were negative correlated with age and generally intercorrelated. We identified protein-coding genes associated with four energetic measures adjusting for age, muscle fiber-ratio, sex and batch effect. Mitochondrial pathways were overrepresented across all energetic variables, albeit with little overlap at the gene level. Alternative spliced transcript isoforms associated with energetics were primarily enriched for cytoplasmic ribonucleoprotein granules. The splicing pathway was up-regulated with aging in low but not in high fitness participants, and transcript isoforms detected in the low fitness group pertain to processes such as cell cycle regulation, RNA/protein localization, nuclear transport and catabolism.
CONCLUSIONS: A consistent mitochondrial signature emerged across all energetic measures. Alternative splicing was enhanced in older, low fitness participants supporting the energy-splicing axis hypothesis. The identified splicing variants were enriched in pathways involving the accumulation of ribonucleoproteins in cytoplasmic granules, whose function remains unclear. Further research is needed to understand the function of these proteoforms in promoting adaptation to low energy availability.

Keywords:  VO2; aging; alternative splicing; energy; exercise; kPCr; mitochondria respirometry; muscle; physical activity

DOI:  https://doi.org/10.1002/jcsm.13603