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Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling.

ABSTRACT: Older individuals have a reduced capacity to induce muscle hypertrophy with resistance exercise (RE), which may contribute to the age-induced loss of muscle mass and function, sarcopenia. We tested the novel hypothesis that dysregulation of microRNAs (miRNAs) may contribute to reduced muscle plasticity with aging. Skeletal muscle expression profiling of protein-coding genes and miRNA was performed in younger (YNG) and older (OLD) men after an acute bout of RE. 21 miRNAs were altered by RE in YNG men, while no RE-induced changes in miRNA expression were observed in OLD men. This striking absence in miRNA regulation in OLD men was associated with blunted transcription of mRNAs, with only 42 genes altered in OLD men vs. 175 in YNG men following RE, demonstrating a reduced adaptability of aging muscle to exercise. Integrated bioinformatics analysis identified miR-126 as an important regulator of the transcriptional response to exercise and reduced lean mass in OLD men. Manipulation of miR-126 levels in myocytes, in vitro, revealed its direct effects on the expression of regulators of skeletal muscle growth and activation of insulin growth factor 1 (IGF-1) signaling. This work identifies a mechanistic role of miRNA in the adaptation of muscle to anabolic stimulation and reveals a significant impairment in exercise-induced miRNA/mRNA regulation with aging.

SUBMITTER: Rivas DA

PROVIDER: S-EPMC5058318 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling.

Rivas Donato A DA Lessard Sarah J SJ Rice Nicholas P NP Lustgarten Michael S MS So Kawai K Goodyear Laurie J LJ Parnell Laurence D LD Fielding Roger A RA

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140613 9

Older individuals have a reduced capacity to induce muscle hypertrophy with resistance exercise (RE), which may contribute to the age-induced loss of muscle mass and function, sarcopenia. We tested the novel hypothesis that dysregulation of microRNAs (miRNAs) may contribute to reduced muscle plasticity with aging. Skeletal muscle expression profiling of protein-coding genes and miRNA was performed in younger (YNG) and older (OLD) men after an acute bout of RE. 21 miRNAs were altered by RE in YNG ...[more]

PMID: 24928197

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Project description:A common characteristic of aging is the loss of skeletal muscle (sarcopenia) which can lead to falls and fractures. MicroRNAs (miRNA) are novel post-transcriptional modulators of gene expression with a potential role as a regulator of skeletal muscle mass and function. The purpose of this study was to profile miRNA expression patterns in aging human skeletal muscle using a miRNA array followed by in-depth functional and network analysis. Muscle biopsy samples from 36 men (young: 31Â±2; n=19; older: 73Â±3; n=17) were: 1) analyzed for the expression of miRNAs using a microRNA array 2) validated with Taqman quantitative real-time PCR assays, and 3) identified (and later validated) for potential gene targets using the bioinformatics knowledge base software, Ingenuity Pathways Analysis. We found that 18 miRNAs were differentially expressed in older humans (P<0.05 and >500 expression level). The Let-7 family members, Let-7b and Let-7e, were significantly elevated and further validated in older subjects (P<0.05). Functional and network analysis from Ingenuity determined that gene targets of the Let-7âs were associated with molecular networks involved in cell cycle control such as cellular proliferation and differentiation. We confirmed with real-time PCR that the mRNA expression of the cell cycle regulators, CDK6, CDC25A and CDC34 were downregulated in older subjects compared to the young (P<0.05). These data suggest that aging is characterized by an increased expression of Let-7 family members which may downregulate genes related to cellular proliferation. We propose that the increased Let-7 expression in older human muscle may be an indicator of impaired cell cycle function. We analyzed skeletal muscle biopsy samples from 19 young and 17 older male subjects that have participated in our previous and current research experiments. The subjects were not engaged in any regular exercise training at the time of the enrollment; however they were physically independent and overall healthy. Screening of subjects were performed with clinical history, physical exam, and laboratory tests including complete blood count with differential, liver and kidney function tests, coagulation profile, fasting blood glucose and oral glucose tolerance test, hepatitis B and C screening, HIV test, TSH, urinalysis, and drug screening. All subjects gave informed written consent before participating in the study, which was approved by the Institutional Review Board of the University of Texas Medical Branch (which is in compliance with the Declaration of Helsinki). Once recruited, a dual-energy X-ray absorptiometry (DEXA) scan (Hologic QDR 4500W, Bedford, MA) was performed to measure body composition and lean mass. Study design. All subjects were admitted to the Clinical Research Center the day prior to the experiment, were provided a standardized dinner and were studied following an overnight fast under basal conditions. Subjects were studied during the same time of day to avoid potential circadian changes and refrained from exercise 48h prior to study participation. A muscle biopsy was obtained from the vastus lateralis of the leg. The biopsy was performed using a 5 mm BergstrÃ¶m biopsy needle, under sterile procedure and local anesthesia (1% lidocaine). Muscle biopsy sample was immediately blotted and frozen in liquid nitrogen and stored at -80oC until analysis. The muscle biopsy sample was used for microRNA and gene analysis.

Project description:BackgroundExercise is an affordable and practical strategy to alleviate several detrimental outcomes from the aging process, including sarcopenia. The elucidation of molecular mechanisms to alleviate sarcopenia is one of the most important steps towards understanding human aging. Although microRNAs (miRNAs) regulate muscle growth, regeneration and aging, the potential role of exercise-mediated miRNAs during the prevention and rehabilitation of skeletal muscle atrophy upon exercise interventions remains unclear.MethodsA miRNA profile by miRNA sequencing for gastrocnemius muscle of a 24-month-old aged male rat model mimicking the naturally aging process was established through screening the differentially expressed miRNAs (DEMs) for alleviating aging-induced skeletal muscle atrophy upon optimal exercise intervention. The screened miRNAs and hub genes, as well as biomarkers with the most significantly enriched pathways, were validated by quantitative real-time polymerase chain reaction and western blotting.ResultsThe sarcopenia index (SI) value and cross-sectional area (CSA) of rats from the old control (OC) group significantly decreased when compared with the youth control (YC) group (P < 0.001, P < 0.01), whereas an increased SI value and an enlarged CSA of rats from the old-aerobic exercise (OE), old-resistance exercise (OR) and old-mixed exercise (OM) groups were determined (P < 0.01, P < 0.001, P < 0.05; P < 0.01, P < 0.01, P < 0.05). Our results demonstrate that 764 known miRNAs, 201 novel miRNAs and 505 miRNA-mRNA interaction networks were identified to be related to aging-induced muscular atrophy. Among them, 13 miRNAs were differentially expressed (P < 0.05 and log2 |fold change| > 1) between the YC group and the OC group. Compared with the OC group, 7, 2 and 11 miRNAs were differentially expressed in the OE, OR and OM groups after exercise interventions, respectively. Meanwhile, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the identified DEMs were primarily related to apoptosis, autophagy and the NF-κB/MuRF1 signalling pathways (P < 0.05). Meanwhile, four DEMs (miR-7a-1-3p, miR-135a-5p, miR-151-5p and miR-196b-5p), six hub genes (Ar, Igf1, Hif1a, Bdnf, Fak and Nras) and several biomarkers (LC3, Beclin1, p62, Bax, Bcl-2 and NF-κB/MuRF1) with the most significantly enriched pathways were confirmed, which may play a key role in muscular atrophy during the aging process.ConclusionsThese findings are closely correlated with the progression of sarcopenia and could act as potential biomarkers for the diagnosis and interventional monitoring of aging-induced skeletal muscle atrophy.

Project description:Skeletal muscle exerts many beneficial effects on the human body including the contraction-dependent secretion of peptides termed myokines. We have recently connected the myokine secreted protein acidic and rich in cysteine (SPARC) to the formation of intramuscular adipose tissue (IMAT) in skeletal muscle from aged mice and humans. Here, we searched for inducers of SPARC in order to uncover novel treatment approaches for IMAT. Endurance exercise in mice as well as forskolin treatment in vitro only modestly activated SPARC levels. However, through pharmacological treatments in vitro, we identified IGF-I as a potent inducer of SPARC expression in muscle cells, likely through a direct activation of its promoter via phosphatidylinositol 4,5-bisphospate 3-kinase (PI3K)-dependent signaling. We employed two different mouse models of growth hormone (GH)/IGF-I deficiency to solidify our understanding of the relationship between IGF-I and SPARC in vivo. GH administration robustly increased intramuscular SPARC levels (3.5-fold) in GH releasing hormone receptor-deficient mice and restored low intramuscular SPARC expression in skeletal muscle from aged mice. Intramuscular glycerol injections induced higher levels of adipocyte markers (adiponectin, perilipin) in aged compared to young mice, which was not prevented by GH treatment. Our study provides a roadmap for the study of myokine regulation during aging and demonstrates that the GH/IGF-I axis is critical for SPARC expression in skeletal muscle. Although GH treatment did not prevent IMAT formation in the glycerol model, targeting SPARC by exercise or by activation of IGF-I signaling might offer a novel therapeutic strategy against IMAT formation during aging. KEY MESSAGES : IGF-I regulates the myokine SPARC in muscle cells directly at the promoter level. GH/IGF-I is able to restore the decreased SPARC levels in aged skeletal muscle. The glycerol model induces higher adipocyte markers in aged compared to young muscle. GH treatment does not prevent IMAT formation in the glycerol model.

Dataset Information

Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling.

Publications

Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling.

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