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Increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related decline in muscle function, and reduces muscle plasticity

ABSTRACT: Increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related decline in muscle function, and reduces muscle plasticity

PROVIDER: PRJNA1023162 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26252455_1.fastq.gz	Fastqsanger.gz
	SRR26252455_2.fastq.gz	Fastqsanger.gz
	SRR26252456_1.fastq.gz	Fastqsanger.gz
	SRR26252456_2.fastq.gz	Fastqsanger.gz
	SRR26252457_1.fastq.gz	Fastqsanger.gz

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Increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related decline in muscle function, and reduces muscle plasticity

Project description:Loss of muscle mass and function—a hallmark of skeletal muscle aging—is known as sarcopenia. Moreover, mammalian aging is reportedly driven by loss of epigenetic information. However, the effect of epigenetic alterations on skeletal muscle homeostasis is unknown. In this study, we show that chronic elevation of global DNA methylation results in a myopathy-like phenotype and age-related changes in skeletal muscle. Overexpression of muscle de novo methyltransferase 3a (Dnmt3a) increased central nucleus-positive myofibers, predominantly in fast-twitch myofibers, and shifted muscle fiber type to stress-resistant slow-twitch myofibers, accompanied by upregulation of chemokine and immune system-related genes and reduced basal autophagy in skeletal muscle. Dnmt3a overexpression reduced muscle androgen receptor signaling, decreased muscle mass and strength, and impaired tolerance to endurance exercise with age. Network analysis identified Akt1 as a potential hub gene. Dnmt3a expression reduced sensitivity to starvation-induced muscle atrophy by suppressing the FoxO-regulated autophagy and ubiquitin–proteasome systems. These data suggest that increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related decline in muscle function, and reduces muscle plasticity.

2025-01-16 | GSE244432 | GEO

Increased global DNA methylation by Dnmt3a disrupts skeletal muscle homeostasis, promotes age-related muscle atrophy, and reduces muscle metabolic elasticity

Project description:Loss of muscle mass and function—a hallmark of skeletal muscle aging—is known as sarcopenia. Moreover, mammalian aging is reportedly driven by loss of epigenetic information. However, the effect of epigenetic alterations on skeletal muscle homeostasis is unknown. In this study, we show that chronic elevation of global DNA methylation results in a myopathy-like phenotype and age-related changes in skeletal muscle. Overexpression of muscle de novo methyltransferase 3a (Dnmt3a) increased central nucleus-positive myofibers, predominantly in fast-twitch myofibers, and shifted muscle fiber type to stress-resistant slow-twitch myofibers, accompanied by increased inflammatory and senescent signatures, decreased mitochondrial OXPHOS complex I protein level, and reduced basal autophagy in skeletal muscle. Chronic Dnmt3a overexpression decreased muscle mass and strength, and impaired tolerance to endurance exercise with age. This age-related decline in endurance exercise capacity was accompanied by an augmented inflammatory signature in a manner that is enhanced with age and promoted muscle atrophy. Network analysis identified Akt1 as a potential hub gene. Dnmt3a expression not only reduced sensitivity to starvation-induced muscle atrophy by suppressing the FoxO-regulated autophagy and ubiquitin–proteasome systems, but also reduced the restorability from starvation-induced muscle atrophy. These data suggest that increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related muscle atrophy, and reduces muscle metabolic elasticity.

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Increased global DNA methylation by Dnmt3a disrupts skeletal muscle homeostasis, promotes age-related muscle atrophy, and reduces muscle metabolic elasticity

Project description:Increased global DNA methylation by Dnmt3a disrupts skeletal muscle homeostasis, promotes age-related muscle atrophy, and reduces muscle metabolic elasticity

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Aging disrupts gene expression timing during muscle regeneration

Project description:Aging disrupts gene expression timing during muscle regeneration

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Aging disrupts gene expression timing during muscle regeneration

Project description:Skeletal muscle function and regenerative capacity decline during aging, yet factors driving these changes are incompletely understood. Muscle regeneration requires temporally coordinated transcriptional programs to drive myogenic stem cells to activate, proliferate, fuse to form myofibers, and to mature myonuclei, restoring muscle function after injury. We assessed global changes in myogenic transcription programs distinguishing muscle regeneration in aged mice from young mice by comparing pseudotime trajectories from single-nucleus RNA sequencing of myogenic nuclei. Aging-specific differences in coordinating myogenic transcription programs necessary for restoring muscle function occur following muscle injury, likely contributing to compromised regeneration in aged mice. Differences in pseudotime alignment of myogenic nuclei when comparing aged to young mice via Dynamic Time-Warping revealed pseudotemporal differences becoming progressively more severe as regeneration proceeds. Disruptions in timing of myogenic gene expression programs may contribute to incomplete skeletal muscle regeneration and declines in muscle function as organisms age.

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Project description:Circadian rhythms are central to optimal physiological functioning and their interruption contributes to the development of several chronic diseases. Alcohol (EtOH) intoxication disrupts circadian rhythms within liver, brain, and intestines, but it is unknown whether alcohol also disrupts components of the core clock in skeletal muscle. Female C57BL/6Hsd mice were randomized to receive either saline (control) or alcohol (EtOH) (5g/kg) via intraperitoneal injection at the start of the dark cycle (ZT12), and gastrocnemius was collected every 4hr from Control and EtOH treated mice for the next 48hr following isoflurane anesthetization. In addition, metyrapone was administered prior to alcohol intoxication in separate mice to determine whether the alcohol-induced increase in serum corticosterone contributed to circadian gene regulation. Finally, synchronized C2C12 myotubes were treated with alcohol (100mM) to assess the influence of centrally or peripherally mediated effects of alcohol on the muscle clock. Alcohol significantly disrupted the mRNA expression of Bmal1, Per1/2, and Cry1/2 in addition to perturbing the clock-controlled genes, Myod1, Dbp, Tef, and Bhlhe40 (p<0.05). Alcohol increased serum corticosterone levels and glucocorticoid target genes, Redd1 and Klf15, in muscle. Metyrapone decreased serum corticosterone in EtOH mice but did not normalize the mRNA expression of Per1, Cry1 and Cry2 and Myod1 which were altered by EtOH. Alcohol did not alter core clock gene expression (Bmal, Per1/2, Cry1/2) at 4, 8, and 12hrs post treatment in synchronized C2C12 myotubes. Therefore, binge alcohol disrupted genes of the core molecular clock independently of elevated serum corticosterone.

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GRSF1 deficiency in skeletal muscle reduces endurance in aged mice

Project description:GRSF1 is a mitochondrial RNA-binding protein important for maintaining mitochondrial function. We found that GRSF1 is highly expressed in cultured skeletal myoblasts differentiating into myotubes. To understand the physiological function of GRSF1 in vivo, we generated mice in which GRSF1 was specifically ablated in skeletal muscle. The conditional knockout mice (Grsf1cKO) appeared normal until 7-9 months of age. Importantly, however, a reduction of muscle endurance compared to wild-type controls was observed in 16- to18-month old Grsf1cKO mice. Transcriptomic analysis revealed more than 200 mRNAs differentially expressed in Grsf1cKO muscle at this age. Notably, mRNAs encoding proteins involved in mitochondrial function, inflammatory reaction, and ion transport, including Mgarp, Cxcl10, Nfkb2, and Sln, were significantly elevated in aged Grsf1cKO muscle. Our findings suggest that GRSF1 deficiency exacerbates the functional decline of aged skeletal muscle, likely through multiple downstream genes.

2021-07-08 | GSE172311 | GEO

Skeletal muscle “ex vivo” mitochondrial respiration parallels decline in vivo oxidative capacity, cardiorespiratory fitness and muscle strength: the Baltimore Longitudinal Study of Aging.

Project description:Mitochondrial function in human skeletal muscle declines with aging, possibly because of damage accumulation caused by reactive oxygen species (ROS) produced during oxidative phosphorylation. However, most evidence for such a decline comes from studies based on indirect methods and the clinical relevance of this decline with respect to physical function has not been clearly delineated. We hypothesized that mitochondrial respiration objectively assessed in permeabilized human muscle fibers declines with aging, correlates with phosphocreatine post exercise recovery rate (kPCr) assessed by 31P magnetic resonance spectroscopy (MRS) and with muscle performance and aerobic fitness. Mitochondrial respiration was assessed by high resolution respirometry in saponin-permeabilized fibers from vastus lateralis muscle biopsies of 38 participants from the Baltimore Longitudinal Study of Aging (BLSA) (21 men, age 24-91 years) who also had available measures of peak oxygen consumption (VO2max) from treadmill tests, gait speed in different tasks, 31P magnetic resonance spectroscopy and isokinetic knee extension strength. Results indicated a significant reduction in mitochondrial respiration in older age (p<0.05) that was independent of potential confounders. Mitochondrial respiratory capacity was also associated with VO2max, muscle strength, phosphocreatine post-exercise recovery rate (kPCr), and time in 400m walk (p < 0.05). A moderate negative trend toward significance (p = 0.074) was observed between mitochondrial respiration and BMI. Finally, transcriptional profiling revealed a downregulation of mitochondrial gene networks with aging (p < 0.05). Overall, our findings reinforce the notion that mitochondrial function declines with age and is implicated in the parallel decline of muscle performance and cardiorespiratory fitness.

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GRSF1 deficiency in skeletal muscle reduces endurance in aged mice

Project description:GRSF1 deficiency in skeletal muscle reduces endurance in aged mice

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Binge Alcohol Disrupts Skeletal Muscle Core Molecular Clock Independent of Glucocorticoids

Project description:Binge Alcohol Disrupts Skeletal Muscle Core Molecular Clock Independent of Glucocorticoids

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