bims-musmir 2024-07-07 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–07–07
nine papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Insights into the epitranscriptomic role of N6-methyladenosine on aging skeletal muscle.
Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.
NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis.
MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.
FOXO-regulated DEAF1 controls muscle regeneration through autophagy.
Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.
Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training.
Reactive oxygen species in skeletal muscle injury, fatigue, regeneration and ageing: In memory of John Faulkner The role of zinc and matrix metalloproteinases in myofibrillar protein degradation in critical illness myopathy.
The impact of aerobic exercise timing on BMAL1 protein expression and antioxidant responses in skeletal muscle of mice.

Biomed Pharmacother. 2024 Jul 03. pii: S0753-3322(24)00925-9. [Epub ahead of print]177 117041

Insights into the epitranscriptomic role of N6-methyladenosine on aging skeletal muscle.

Susan Enechojo Ogbe, JiDa Wang, YueXuan Shi, Ying Wang, Zhe Xu, Joseph Kofi Abankwa, Lisa Dal Pozzo, ShuWu Zhao, HuiFang Zhou, YanFei Peng, XiaoQian Chu, XiangLing Wang, YuHong Bian.

  The modification of RNA through the N6-methyladenosine (m6A) has emerged as a growing area of research due to its regulatory role in gene expression and various biological processes regulating the expression of genes. m6A RNA methylation is a post-transcriptional modification that is dynamic and reversible and found in mRNA, tRNA, rRNA, and other non-coding RNA of most eukaryotic cells. It is executed by special proteins known as "writers," which initiate methylation; "erasers," which remove methylation; and "readers," which recognize it and regulate the expression of the gene. Modification by m6A regulates gene expression by affecting the splicing, translation, stability, and localization of mRNA. Aging causes molecular and cellular damage, which forms the basis of most age-related diseases. The decline in skeletal muscle mass and functionality because of aging leads to metabolic disorders and morbidities. The inability of aged muscles to regenerate and repair after injury poses a great challenge to the geriatric populace. This review seeks to explore the m6A epigenetic regulation in the myogenesis and regeneration processes in skeletal muscle as well as the progress made on the m6A epigenetic regulation of aging skeletal muscles.

Keywords:  aging; epigenetics; m(6)A methylation; regeneration; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1016/j.biopha.2024.117041
Physiol Rep. 2024 Jul;12(13): e16103

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.

Brian A Hain, Scot R Kimball, David L Waning.

  Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.

Keywords:  cancer cachexia; mitochondria; nicotinic acid; oxidative stress; sirtuin‐1

DOI:  https://doi.org/10.14814/phy2.16103
medRxiv. 2024 Jun 16. pii: 2024.06.15.24308845. [Epub ahead of print]

NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis.

Elie Naddaf, Thi Kim Oanh Nguyen, Jens O Watzlawik, Huanyao Gao, Xu Hou, Fabienne C Fiesel, Jay Mandrekar, Eileen Kokesh, William S Harmsen, Ian R Lanza, Wolfdieter Springer, Eugenia Trushina.

Background: Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients, highlighting sex differences.
Methods: We included 38 IBM patients and 22 age- and sex-matched controls without myopathy. Bulk RNA sequencing, Meso Scale Discovery ELISA, western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.
Results: We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated. On muscle histopathology, there is increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction-NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy, most significantly in males, with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction. NLRP3 RNA levels correlated with p-S65-Ubiquitin levels in both sexes but with loss of in muscle strength only in males. Finally, we identified sex-specific molecular pathways in IBM, with females having activation of pathways that could offset some of the pathomechanisms of IBM.
Conclusions: NLRP3 inflammasome is activated in IBM, along with altered mitophagy particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.

DOI: https://doi.org/10.1101/2024.06.15.24308845
FEBS J. 2024 Jun 30.

MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.

Eddie Tam, Khang Nguyen, Hye Kyoung Sung, Gary Sweeney.

  Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the CDGSH iron-sulfur domain-containing protein 1 (CISD1, also known as mitoNEET) (mitoN) protein, we examined the potential role of MitoN in preventing IO-induced insulin resistance. In L6 control cells, IO resulted in insulin resistance which could be prevented by MitoN as demonstrated by western blot of p-Akt and Akt biosensor cells. Mechanistically, IO increased; mitochondrial iron accumulation, mitochondrial reactive oxygen species (ROS), Fis1-dependent mitochondrial fission, mitophagy, FUN14 domain-containing protein 1 (FUNDC1) expression, and decreased Parkin. MitoN overexpression was able to reduce increases in mitochondrial iron accumulation, mitochondrial ROS, mitochondrial fission, mitophagy and FUNDC1 upregulation due to IO. MitoN did not have any effect on the IO-induced downregulation of Parkin. MitoN alone also upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) protein levels, a master regulator of mitochondrial biogenesis. The use of mitochondrial antioxidant, Skq1, or fission inhibitor, Mdivi-1, prevented IO-induced insulin resistance implying both mitochondrial ROS and fission play a causal role in the development of insulin resistance. Taken together, MitoN is able to confer protection against IO-induced insulin resistance in L6 skeletal muscle cells through regulation of mitochondrial iron content, mitochondrial ROS, and mitochondrial fission.

Keywords:  insulin resistance; iron overload; mitoNEET; mitochondria; mitochondrial dynamics; reactive oxygen species

DOI:  https://doi.org/10.1111/febs.17214
Autophagy. 2024 Jul 04.

FOXO-regulated DEAF1 controls muscle regeneration through autophagy.

Kah Yong Goh, Wen Xing Lee, Sze Mun Choy, Gopal Krishnan Priyadarshini, Kenon Chua, Qian Hui Tan, Shin Yi Low, Hui San Chin, Chee Seng Wong, Shu-Yi Huang, Nai Yang Fu, Jun Nishiyama, Nathan Harmston, Hong-Wen Tang.

  The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.

Keywords:  Autophagy; Deaf1; FOXO; cancer cachexia; muscle; sarcopenia

DOI:  https://doi.org/10.1080/15548627.2024.2374693
J Appl Physiol (1985). 2024 Jul 04.

Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Nathan R Kerr, Chandler W Mossman, Chih-Hsuan Chou, Joshua M Bunten, Taylor J Kelty, Thomas E Childs, R Scott Rector, W David Arnold, Laurel A Grisanti, Xiangwei Du, Frank W Booth.

  Alzheimer's Disease (AD) is the 5th leading cause of death in older adults and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a 3-fold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse (via a model of hindlimb immobilization (HLI)) on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-month-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of APP and tau protein in the hippocampus, 4) and reduced BDNF expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.

Keywords:  Muscle disuse; brain insulin resistance; hippocampus; iron overload; muscle-brain axis

DOI:  https://doi.org/10.1152/japplphysiol.00234.2024
Mol Metab. 2024 Jun 29. pii: S2212-8778(24)00111-X. [Epub ahead of print] 101980

Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training.

Mark R Viggars, Hannah E Berko, Stuart J Hesketh, Christopher A Wolff, Miguel A Gutierrez-Monreal, Ryan A Martin, Isabel G Jennings, Zhiguang Huo, Karyn A Esser.

   OBJECTIVE: In this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodeling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice.
METHODS: Combining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise.
RESULTS: Muscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including Nr4a3 and Ppargc1a. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of 'exercise-training' responsive genes shared for each tissue between genotypes.
CONCLUSIONS: Our investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle and its likely impact on the system plays in the peripheral tissue adaptations to exercise training. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased gene expression signatures of inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.

Keywords:  Circadian biology; Exercise; Inflammation; Metabolism; Signal transduction; Transcription

DOI:  https://doi.org/10.1016/j.molmet.2024.101980
Free Radic Biol Med. 2024 Jun 27. pii: S0891-5849(24)00539-2. [Epub ahead of print]

Reactive oxygen species in skeletal muscle injury, fatigue, regeneration and ageing: In memory of John Faulkner The role of zinc and matrix metalloproteinases in myofibrillar protein degradation in critical illness myopathy.

Fernando Ribeiro, Xiang Zhang, Ya Wen, Nicola Cacciani, Yvette Hedström, Zhidan Xia, Richard Schulz, Lars Larsson.

  Due to an unexpected activation of different zinc (Zn) transporters in a recent prospective clinical study, we have revisited the role of Zn homeostasis and the activation of matrix metalloproteinases (MMPs) in skeletal muscle exposed to the intensive care unit (ICU) condition (immobilization and mechanical ventilation). ICU patients exposed to 12 days ICU condition were followed longitudinally with six repeated muscle biopsies while they showed a progressive preferential myosin loss, i.e., the hallmark of Critical Illness Myopathy (CIM), in parallel with the activation of Zn-transporters. In this study, we have revisited the expression of Zn-transporters and the activation of MMPs in clinical as well as in experimental studies using an established ICU model. MMPs are a group Zn-dependent endopeptidases which do not only target and cleave extracellular proteins but also intracellular proteins including multiple sarcomeric proteins. MMP-9 is of specific interest since the hallmark of CIM, the preferential myosin loss, has also been reported in dilated cardiomyopathy and coupled to MMP-9 activation. Transcriptional activation of Zn-transporters was observed in both clinical and experimental studies as well as the activation of MMPs, in particular MMP-9, in various limb and respiratory muscles in response to long-term exposure to the ICU condition. The activation of Zn-transporters was paralleled by increased Zn levels in skeletal muscle which in turn showed a negative linear correlation with the preferential myosin loss associated with CIM, offering a potential intervention strategy. Thus, activation of Zn-transporters, increased intramuscular Zn levels, and activation of the Zn-dependent MMPs are forwarded as a probable mechanism involved in CIM pathophysiology. These effects were confirmed in different rat strains subjected to a model of CIM and exacerbated by old age. This is of specific interest since old age and muscle wasting are the two factors most strongly associated with ICU mortality.

Keywords:  Intensive care; Mechanical ventilation; Metallothionein; Myosin; Zinc transporters

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.022
Free Radic Res. 2024 Jul 01. 1-12

The impact of aerobic exercise timing on BMAL1 protein expression and antioxidant responses in skeletal muscle of mice.

Lei Xu, Jie Jia, Jingjing Yu, Shudan Miao, Ying Zhang.

  It is well known that the adaptations of muscular antioxidant system to aerobic exercise depend on the frequency, intensity, duration, type of the exercise. Nonetheless, the timing of aerobic exercise, related to circadian rhythms or biological clock, may also affect the antioxidant defense system, but its impact remains uncertain. Bain and muscle ARNT-like 1 (BMAL1) is the core orchestrator of molecular clock, which can maintain cellular redox homeostasis by directly controlling the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2). So, our research objective was to evaluate the impacts of aerobic exercise training at various time points of the day on BMAL1 and NRF2-mediated antioxidant system in skeletal muscle. C57BL/6J mice were assigned to the control group, the group exercising at Zeitgeber Time 12 (ZT12), and the group exercising at ZT24. Control mice were not intervened, while ZT12 and ZT24 mice were trained for four weeks at the early and late time point of their active phase, respectively. We observed that the skeletal muscle of ZT12 mice exhibited higher total antioxidant capacity and lower reactive oxygen species compared to ZT24 mice. Furthermore, ZT12 mice improved the colocalization of BMAL1 with nucleus, the protein expression of BMAL1, NRF2, NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, glutamate-cysteine ligase modifier subunit and glutathione reductase in comparison to those of ZT24 mice. In conclusion, the 4-week aerobic training performed at ZT12 is more effective for enhancing NRF2-mediated antioxidant responses of skeletal muscle, which may be attributed to the specific activation of BMAL1.

Keywords:  BMAL1; Exercise timing; NRF2-mediated antioxidant responses; skeletal muscle

DOI:  https://doi.org/10.1080/10715762.2024.2348789