Role of PDK1 in Skeletal Muscle Hypertrophy Induced by Exercise Load
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE150464 | GEO | 2020/05/14
REPOSITORIES: GEO
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Project description:Role of PDK1 in Skeletal Muscle Hypertrophy Induced by Exercise Load
| PRJNA632500 | ENA
Project description:Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers.
2021-08-27 | PXD028167 | iProX
Project description:This project consisted of three HDX-MS experiments. First, we compared the dimeric PDK1(SKD-PIF) to monomeric PDK1(SKD) and mapped the differences in deuterium incorporation onto the dimer model. We then compared the deuterium incorporation kinetics for the kinase (PDK1(SKD)) and PH (PDK1(PH) domains of PDK1 with full-length PDK1 (PDK1(FL)) in pairwise experiments.
2022-05-20 | PXD027401 | Pride
Project description:Mechanosensing is required for the senses of touch and hearing, and impacts on cellular processes such as cell differentiation, migration, invasion and tissue homeostasis. Mechanical inputs give rise to p38- and JNK-signaling, which mediates adaptive physiological responses in various tissues. In muscle, fiber contraction-induced p38 and JNK signaling ensures adaptation to exercise, muscle repair and hypertrophy. However, the mechanism by which muscle fibers sense mechanical load to activate this signaling, as well as the physiological roles of mechanical stress sensing more broadly, have remained elusive. Here, we show that the upstream MAP3K ZAK is a sensor of cellular compression induced by osmotic shock and cyclic compression in vitro, and muscle contraction in vivo. This function relies on ZAK’s ability to recognize stress fibers in cells and the corresponding Z-discs in muscle fibers, when under tension. Consequently, ZAK-deficient mice present with skeletal muscle defects characterized by fibers with centralized nuclei and progressive adaptation towards a slower myosin profile. Our results highlight how cells in general sense mechanical compressive load, and how mechanical forces generated during muscle contraction are translated into MAP kinase signaling.
2022-05-31 | PXD028548 | Pride
Project description:The adult skeletal muscle is a plastic tissue with a remarkable ability to adapt to different levels of activity by altering its excitability, its contractile and metabolic phenotype and its mass. Knowledge on the mechanisms responsible for muscle mass comes primarily from models of muscle inactivity or denervation or from genetic models of muscle diseases. Given that the underlying exercise-induced transcriptional mechanisms regulating muscle mass are not fully understood, here we investigated the cellular and molecular adaptive mechanisms taking place in fast skeletal muscle of adult zebrafish in response to swimming. Fish were trained at low swimming speed (0.1 m/s; non-exercised) or at their optimal swimming speed (0.4 m/s; exercised). A significant increase in fibre cross-sectional area (1,290 M-BM-1 88 vs. 1,665 M-BM-1 106 M-NM-<m2) and vascularization (298 M-BM-1 23 vs. 458 M-BM-1 38 capillaries/mm2) was found in exercised over non-exercised fish. Gene expression profiling evidenced the transcriptional activation of a series of complex networks of extracellular and intracellular signaling molecules and pathways involved in the regulation of muscle mass, myogenesis and angiogenesis, many (e.g. BMP, TGFM-oM-^AM-", FGF, Notch, Wnt, MEF2, Shh, EphrinB2) not previously associated with exercise-induced contractile activity, and that recapitulate in part the transcriptional events occurring during skeletal muscle regeneration. These results demonstrate that fibre hypertrophy is responsible for the growth-promoting effects of exercise accompanied by a switch to a more oxidative capacity of white muscle fibres to fuel the increased energy demands. Importantly, our study identified novel molecular mechanisms regulating muscle mass and function in vertebrates. Adult zebrafish were subjected or not to a swim training regime consisting of swimming at the optimal swimming speed for this species for 6 h/day, 5 days/week for a total of 4 weeks (20 experimental days). Total RNA of fast muscle from individual non-exercised (n = 8) and exercised (n = 8) zebrafish was analyzed.
2014-12-23 | E-GEOD-58929 | biostudies-arrayexpress
Project description:The adaptation of regimented exercise in skeletal muscle including muscular hypertrophy and enhanced strength decline significantly with aging. Transcriptome analysis following RNA sequencing reveals extensive activation of hypoxia-related genes in young exercised mice versus the sedentary, but absent in aged exercised mice. Particularly, less expression of aryl hydrocarbon receptor translocator (ARNT) was observed in response to exercise in aged mice. Young mice underwent skeletal muscle-specific knockout of ARNT (ARNT mKO) obtain deficient benefit from exercise resembling the aged mice. The deletion of ARNT associated with decreased expression of Notch1 intracellular domain(N1ICD) impair muscle hypertrophy and regeneration. Administration of ML228, a systematic agonist of ARNT, rescued skeletal muscle adaptabilities in old mice, which was suppressed by administrating N1ICD inhibitor(DAPT). These results suggest that the loss of skeletal muscle ARNT is partially responsible for diminished response to exercise in aging and activation of hypoxia signaling holds promise for rescuing the adaptability in aged muscle.
2021-12-31 | GSE155937 | GEO
Project description:The adult skeletal muscle is a plastic tissue with a remarkable ability to adapt to different levels of activity by altering its excitability, its contractile and metabolic phenotype and its mass. Knowledge on the mechanisms responsible for muscle mass comes primarily from models of muscle inactivity or denervation or from genetic models of muscle diseases. Given that the underlying exercise-induced transcriptional mechanisms regulating muscle mass are not fully understood, here we investigated the cellular and molecular adaptive mechanisms taking place in fast skeletal muscle of adult zebrafish in response to swimming. Fish were trained at low swimming speed (0.1 m/s; non-exercised) or at their optimal swimming speed (0.4 m/s; exercised). A significant increase in fibre cross-sectional area (1,290 ± 88 vs. 1,665 ± 106 μm2) and vascularization (298 ± 23 vs. 458 ± 38 capillaries/mm2) was found in exercised over non-exercised fish. Gene expression profiling evidenced the transcriptional activation of a series of complex networks of extracellular and intracellular signaling molecules and pathways involved in the regulation of muscle mass, myogenesis and angiogenesis, many (e.g. BMP, TGF, FGF, Notch, Wnt, MEF2, Shh, EphrinB2) not previously associated with exercise-induced contractile activity, and that recapitulate in part the transcriptional events occurring during skeletal muscle regeneration. These results demonstrate that fibre hypertrophy is responsible for the growth-promoting effects of exercise accompanied by a switch to a more oxidative capacity of white muscle fibres to fuel the increased energy demands. Importantly, our study identified novel molecular mechanisms regulating muscle mass and function in vertebrates.
2014-12-23 | GSE58929 | GEO
Project description:It is unknown if adult human skeletal muscle has an epigenetic memory of earlier encounters with growth. We report, for the first time in humans, genome-wide DNA methylation (850,000CpGs) and gene expression analysis after muscle hypertrophy (loading), return of muscle mass to baseline (unloading), followed by later hypertrophy (reloading). We discovered increased frequency of hypomethylation across the genome after reloading (18,816 CpGs) versus earlier loading (9,153 CpG sites). We also identified AXIN1, GRIK2, CAMK4, TRAF1 as hypomethylated genes with enhanced expression after loading that maintained their hypomethylated status even during unloading where muscle mass returned to control levels, indicating a memory of these genes methylation signatures following earlier hypertrophy. Further, UBR5, RPL35a, HEG1, PLA2G16, SETD3 displayed hypomethylation and enhanced gene expression following loading, and demonstrated the largest increases in hypomethylation, gene expression and muscle mass after later reloading, indicating an epigenetic memory in these genes. Finally, genes; GRIK2, TRAF1, BICC1, STAG1 were epigenetically sensitive genes demonstrating hypomethylation after a single bout of resistance exercise that was maintained 22 weeks later with the largest increase in gene expression and muscle mass after reloading. Overall, we identify an important epigenetic role for a number of largely unstudied genes in muscle hypertrophy/ memory.
2018-05-23 | GSE114763 | GEO
Project description:Northern elephant seals (NES, Mirounga angustirostris) undergo an annual molt during which they spend ~40 days fasting on land with reduced activity and lose approximately one-quarter of their body mass. Reduced activity and muscle load in stereotypic terrestrial mammalian models results in decreased muscle mass and capacity for force production and aerobic metabolism. However, the majority of lost mass in fasting female NES is from fat while muscle mass is largely preserved. Although muscle mass is preserved, potential changes to the metabolic and contractile capacity are unknown. To assess potential changes in NES skeletal muscle during molt, we collected muscle biopsies from 6 adult female NES at the beginning of the molt and after ~30 days at the end of the molt. Skeletal muscle was assessed for respiratory capacity using high resolution respirometry, and RNA was extracted to assess changes in gene expression. Despite a month of reduced activity, fasting, and weight loss, skeletal muscle respiratory capacity was preserved with no change in OXPHOS respiratory capacity. Molt was associated with 162 upregulated genes including genes favoring lipid metabolism and regulating cell cycles. We identified 172 downregulated genes including those coding for ribosomal proteins and genes associated with skeletal muscle force transduction and glucose metabolism. Following ~30 days of molt, NES skeletal muscle metabolic capacity appears largely preserved although mechanotransduction may be compromised. In the absence of exercise stimulus, fasting-induced shifts in skeletal muscle lipid metabolism may stimulate lipid signaling pathways associated with preserving the mass and metabolic capacity of slow oxidative muscle.
2020-09-15 | GSE151509 | GEO
Project description:Interventions: Experimental group:nutrition and exercise investigation and Intervention;Control Group:nutrition and exercise investigation
Primary outcome(s): Skeletal muscle mass and strength;Nutrition assessment;physical examination
Study Design: Case-Control study
| 47924 | ecrin-mdr-crc