The Role of AMPK in Neuromuscular Biology and Disease

Dial, Athan G.; Ng, Sean Y.; Manta, Alexander; Ljubicic, Vladimir

doi:10.1016/j.tem.2018.02.010

Cited by 34 publications

(54 citation statements)

References 97 publications

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“…, ; Dial et al . ). To further explore this, we employed IF analyses to examine potential exercise‐mediated subcellular translocation of these proteins.…”

Section: Resultsmentioning

confidence: 97%

“…; Dial et al . ). For example, PGC‐1α determines, maintains and remodels neuromuscular phenotype by regulating transcriptional and posttranscriptional events, such as mRNA processing, including splicing (Monsalve et al .…”

Section: Discussionmentioning

confidence: 97%

“…; Dial et al . ). Most recently, work in a pre‐clinical murine model of DM1 demonstrated that chronic exercise improved the spliceopathy of select genes germane to the disorder, such as CLC‐1, sarco/endoplasmic reticulum Ca 2+ ‐ATPase 1 (SERCA) and ryanodine receptor 1 (RYR1; Ravel‐Chapuis et al .…”

Section: Introductionmentioning

confidence: 97%

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Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice

Manta

Stouth

Xhuti

et al. 2019

The Journal of Physiology

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Key pointsr Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting and myotonia.r A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder.r Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable and elicits benefits in muscle strength and function; however, the molecular mechanisms of exercise adaptation in DM1 are undefined.r Our results demonstrate that 7 weeks of volitional running wheel exercise in a pre-clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia.r At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind-like 1 protein from myonuclear foci and improved mRNA alternative splicing.Abstract Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion neuromuscular disorder that is most prominently characterized by skeletal muscle weakness, wasting and myotonia. Chronic physical activity is safe and satisfying, and can elicit functional benefits such as improved strength and endurance in DM1 patients, but the underlying cellular basis of exercise adaptation is undefined. Our purpose was to examine the mechanisms of exercise biology in DM1. Healthy, sedentary wild-type (SED-WT) mice, as well as sedentary human skeletal actin-long repeat animals, a murine model of DM1 myopathy (SED-DM1), and DM1 mice with volitional access to a running wheel for 7 weeks (EX-DM1), were utilized. Chronic exercise augmented strength and endurance in vivo and in situ in DM1 mice. These alterations A. Manta and others J Physiol 597.5 coincided with normalized measures of myopathy, as well as increased mitochondrial content. Electromyography revealed a 70-85% decrease in the duration of myotonic discharges in muscles from EX-DM1 compared to SED-DM1 animals. The exercise-induced enhancements in muscle function corresponded at the molecular level with mitigated spliceopathy, specifically the processing of bridging integrator 1 and muscle-specific chloride channel (CLC-1) transcripts. CLC-1 protein content and sarcolemmal expression were lower in SED-DM1 versus SED-WT animals, but they were similar between SED-WT and EX-DM1 groups. Chronic exercise also attenuated RNA toxicity, as indicated by reduced (CUG) n foci-positive myonuclei and sequestered Muscleblind-like 1 (MBNL1). Our data indicate that chronic exercise-induced physiological improvements in DM1 occur in concert with mitigated primary downstream disease mechanisms, including RNA toxicity, MBNL1 loss-of-function, and alternative mRNA splicing.

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“…, ; Dial et al . ). To further explore this, we employed IF analyses to examine potential exercise‐mediated subcellular translocation of these proteins.…”

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice

Manta

Stouth

Xhuti

et al. 2019

The Journal of Physiology

Self Cite

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“…; Dial et al . ), we utilized transcript levels of PGC‐1α as a functional outcome measure of its enzymatic activity. PGC‐1α mRNA expression in the TA muscle was similar between genotypes at rest and was elevated ∼5‐fold ( P < 0.05) in Smn 2B/− 3 h animals, as compared to all other experimental groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4A and D). Given that PGC-1α autoregulates its gene expression (Handschin et al 2003;Dial et al 2018a), we utilized transcript levels of PGC-1α as a functional outcome measure of its enzymatic activity. PGC-1α mRNA expression in the TA muscle was similar between genotypes at rest and was (Fig.…”

Section: Exercise-induced Ampk-p38-pgc-1α Signallingmentioning

confidence: 99%

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Mikhail

Ljubicic

2019

The Journal of Physiology

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Key points Spinal muscular atrophy (SMA) is a health‐ and life‐limiting neuromuscular disorder caused by a deficiency in survival motor neuron (SMN) protein. While historically considered a motor neuron disease, current understanding of SMA emphasizes its systemic nature, which requires addressing affected peripheral tissues such as skeletal muscle in particular. Chronic physical activity is beneficial for SMA patients, but the cellular and molecular mechanisms of exercise biology are largely undefined in SMA. After a single bout of exercise, canonical responses such as skeletal muscle AMP‐activated protein kinase (AMPK), p38 mitogen‐activated protein kinase (p38) and peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) activation were preserved in SMA‐like Smn2B/− animals. Furthermore, molecules involved in SMN transcription were also altered following physical activity. Collectively, these changes were coincident with an increase in full‐length SMN transcription and corrective SMN pre‐mRNA splicing. This study advances understanding of the exercise biology of SMA and highlights the AMPK–p38–PGC‐1α axis as a potential regulator of SMN expression in muscle. Abstract Chronic physical activity is safe and effective in spinal muscular atrophy (SMA) patients, but the underlying cellular events that drive physiological adaptations are undefined. We examined the effects of a single bout of exercise on molecular mechanisms associated with adaptive remodelling in the skeletal muscle of Smn2B/− SMA‐like mice. Skeletal muscles were collected from healthy Smn2B/+ mice and Smn2B/− littermates at pre‐ (postnatal day (P) 9), early‐ (P13) and late‐ (P21) symptomatic stages to characterize SMA disease progression. Muscles were also collected from Smn2B/− animals exercised to fatigue on a motorized treadmill. Intracellular signalling and gene expression were examined using western blotting, confocal immunofluorescence microscopy, real‐time quantitative PCR and endpoint PCR assays. Basal skeletal muscle AMP‐activated protein kinase (AMPK) and p38 mitogen‐activated protein kinase (p38) expression and activity were not affected by SMA‐like conditions. Canonical exercise responses such as AMPK, p38 and peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) activation were observed following a bout of exercise in Smn2B/− animals. Furthermore, molecules involved in survival motor neuron (SMN) transcription, including protein kinase B (AKT) and extracellular signal‐regulated kinases (ERK)/ETS‐like gene 1 (ELK1), were altered following physical activity. Acute exercise was also able to mitigate aberrant proteolytic signalling in the skeletal muscle of Smn2B/− mice. Collectively, these changes were coincident with an exercise‐evoked increase in full‐length SMN mRNA expression. This study advances our understanding of the exercise biology of SMA and highlights the AMPK–p38–PGC‐1α axis as a potential regulator of SMN expression alongside AKT and ERK/ELK1 signalling.

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PRKAA1 predicts prognosis and is associated with immune characteristics in gastric cancer

Chen¹,

Chen²,

Zhu³

et al. 2023

Funct Integr Genomics

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PRKAA1 is the α-subunit of 5-AMP-activated protein kinase. This study aimed to investigate the role of PRKAA1 expression in multiple clinical parameters, the overall survival rate, blood indexes, and immune in ltration in gastric cancer (GC) patients. MethodsWe investigated PRKAA1 expression data of in GC patients using an ELISA, proteinatlas, ualcan, and GEPIA. PRKAA1 expression was associated with immune cell in ltration, and immune cell types were analyzed with the TIMER, DICE, and proteinatlas databases. We compared the level of PRKAA1 expression based on the clinical features of GC patients (n = 345). GC patients were divided into two groups based on PRKAA1 expression, and the lymphocyte subsets, overall survival rate, and clinical parameters were compared with peripheral blood mononuclear cell and biochemical indexes. ResultsPRKAA1 was highly expressed in the serum of GC patient compared with that of healthy individuals. GC patients with distant metastases, a later TNM stage, and stage IV in UICC exhibited higher PRKAA1 expression. PRKAA1 expression was signi cantly correlated with circulating T cells. The proteinatlas and DICE database results con rmed that PRKAA1 was closely associated with T cells in a single cell cluster. Furthermore, GC patients with low PRKAA1 expression had better OS rates. ConclusionPRKAA1 may serve as a potential prognostic biomarker for GC and have an association with immune in ltrates.

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The Role of AMPK in Neuromuscular Biology and Disease

Cited by 34 publications

References 97 publications

Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice

Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

PRKAA1 predicts prognosis and is associated with immune characteristics in gastric cancer

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