Vitamin C deficiency causes muscle atrophy and a deterioration in physical performance.
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ABSTRACT:
SUBMITTER: Takisawa S
PROVIDER: S-EPMC6426981 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Antibiotics lead to increased susceptibility to colonization by pathogenic organisms, with different effects on the host-microbiota relationship. Here, we show that metronidazole treatment of specific pathogen-free (SPF) mice results in a significant increase of the bacterial phylum Proteobacteria in fecal pellets. Furthermore, metronidazole in SPF mice decreases hind limb muscle weight and results in smaller fibers in the tibialis anterior muscle. In the gastrocnemius muscle, metronidazole causes upregulation of Hdac4, myogenin, MuRF1, and atrogin1, which are implicated in skeletal muscle neurogenic atrophy. Metronidazole in SPF mice also upregulates skeletal muscle FoxO3, described as involved in apoptosis and muscle regeneration. Of note, alteration of the gut microbiota results in increased expression of the muscle core clock and effector genes Cry2, Ror-?, and E4BP4. PPAR? and one of its important target genes, adiponectin, are also upregulated by metronidazole. Metronidazole in germ-free (GF) mice increases the expression of other core clock genes, such as Bmal1 and Per2, as well as the metabolic regulators FoxO1 and Pdk4, suggesting a microbiota-independent pharmacologic effect. In conclusion, metronidazole in SPF mice results in skeletal muscle atrophy and changes the expression of genes involved in the muscle peripheral circadian rhythm machinery and metabolic regulation.
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Project description:The classical renin-angiotensin system (RAS), known as the angiotensin (Ang)-converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, induces various organ damages including cognitive decline. On the other hand, the ACE2/Ang-(1-7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the classical RAS axis in the cardiovascular system. However, the roles of the ACE2/Ang-(1-7)/Mas axis in cognitive function largely remain to be elucidated, and we therefore examined possible roles of ACE2 in cognitive function. Male, 10-week-old C57BL6 (wild type, WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task and Y maze test to evaluate cognitive function. ACE2KO mice exhibited significant impairment of cognitive function, compared with that in WT mice. Superoxide anion production increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit, p22phox, p40phox, p67phox, and gp91phox in the hippocampus of ACE2KO mice compared with WT mice. The protein level of SOD3 decreased in ACE2KO mice compared with WT mice. The AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, the AT2 receptor mRNA level in the hippocampus did not differ between the two strains. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex. Brain-derived neurotrophic factor (BDNF) mRNA and protein levels were lower in the hippocampus in ACE2KO mice compared with WT mice. Taken together, ACE2 deficiency resulted in impaired cognitive function, probably at least in part because of enhanced oxidative stress and a decrease in BDNF.
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Project description:BACKGROUND: The diminished ability of aged muscle to self-repair is a factor behind sarcopenia and contributes to muscle atrophy. Muscle repair depends on satellite cells whose pool size is diminished with aging. A reduction in Notch pathway activity may explain the age-related decrease in satellite cell proliferation, as this pathway has been implicated in satellite cell self-renewal. Skeletal muscle is a target of vitamin D which modulates muscle cell proliferation and differentiation in vitro and stimulates muscle regeneration in vivo. Vitamin D status is positively correlated to muscle strength/function, and elderly populations develop a vitamin D deficiency. The aim of this study was to evaluate how vitamin D deficiency induces skeletal muscle atrophy in old rats through a reduction in Notch pathway activity and proliferation potential in muscle. METHODS: 15-month-old male rats were vitamin D-depleted or not (control) for 9 months (n?=?10 per group). Rats were 24-month-old at the end of the experiment. Gene and/or protein expression of markers of proliferation, or modulating proliferation, and of Notch signalling pathway were studied in the tibialis anterior muscle by qPCR and western blot. An unpaired student's t-test was performed to test the effect of the experimental conditions. RESULTS: Vitamin D depletion led to a drop in concentrations of plasma 25-hydroxyvitamin D in depleted rats compared to controls (-74%, p?<?0.01). Tibialis anterior weight was decreased in D-depleted rats (-25%, p?<?0.05). The D-depleted group showed -39%, -31% drops in expression of two markers known to modulate proliferation (Bmp4, Fgf-2 mRNA levels) and -56% drop in one marker of cell proliferation (PCNA protein expression) compared to controls (p?<?0.05). Notch pathway activity was blunted in tibialis anterior of D-depleted rats compared to controls, seen as a down-regulation of cleaved Notch (-53%, p?<?0.05) and its target Hes1 (-35%, p?<?0.05). CONCLUSIONS: A 9-month vitamin D depletion induced vitamin D deficiency in old rats. Vitamin D depletion induces skeletal muscle atrophy in old rats through a reduction in Notch pathway activity and proliferation potential. Vitamin D deficiency could aggravate the age-related decrease in muscle regeneration capacity.
| S-EPMC4195890 | biostudies-other
Project description:Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1?, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.
| S-EPMC3431665 | biostudies-literature
Project description:Recent studies show that vitamin D deficiency may be responsible for muscle atrophy. The purpose of this study was to investigate markers of muscle atrophy, signalling proteins, and mitochondrial capacity in patients with chronic low back pain with a focus on gender and serum vitamin D level. The study involved patients with chronic low back pain (LBP) qualified for posterior lumbar interbody fusion (PLIF). Patients were divided into three groups: supplemented (SUPL) with vitamin D (3200 IU/day for 5 weeks), placebo with normal levels of vitamin D (SUF), and the placebo group with vitamin D deficiency (DEF). The marker of muscle atrophy including atrogin-1 and protein content for IGF-1, Akt, FOXO3a, PGC-1α, and citrate synthase (CS) activity were determined in collected multifidus muscle. In the paraspinal muscle, IGF-1 levels were higher in the SUF group as compared to both the SUPL and DEF groups (p < 0.05). In the SUPL group, we found significantly increased protein content for pAkt (p < 0.05) and decreased level of FOXO3a (p < 0.05). Atrogin-1 content was significantly different between men and women (p < 0.05). The protein content of PGC-1α was significantly higher in the SUF group as compared to the DEF group (p < 0.05). CS activity in the paraspinal muscle was higher in the SUPL group than in the DEF group (p < 0.05). Our results suggest that vitamin D deficiency is associated with elevated oxidative stress, muscle atrophy, and reduced mitochondrial function in the multifidus muscle. Therefore, vitamin D-deficient LBP patients might have reduced possibilities on early and effective rehabilitation after PLIF surgery.
| S-EPMC6589343 | biostudies-literature
Project description:Activin A (ActA) is considered to play a major role in cancer-induced cachexia (CC). Indeed, circulating ActA levels are elevated and predict survival in patients with CC. However, the mechanisms by which ActA mediates CC development and in particular skeletal muscle (SM) atrophy in humans are not yet fully understood. In this work, we aimed to investigate the effects of ActA on human SM and in mouse models of CC. We used a model of human muscle cells in culture to explore how ActA acts towards human SM. In this model, recombinant ActA induced myotube atrophy associated with the decline of MyHC-β/slow, the main myosin isoform in human muscle cells studied. Moreover, ActA inhibited the expression and activity of MEF2C, the transcription factor regulating MYH7, the gene which codes for MyHC-β/slow. This decrease in MEF2C was involved in the decline of MyHC-β/slow expression, since inhibition of MEF2C by a siRNA leads to the decrease in MyHC-β/slow expression. The relevance of this ActA/MEF2C pathway in vivo was supported by the parallel decline of MEF2C expression and SM mass, which are both blunted by ActA inhibition, in animal models of CC. In this work, we showed that ActA is a potent negative regulator of SM mass by inhibiting MyHC-β/slow synthesis through downregulation of MEF2C. This observation highlights a novel interaction between ActA signaling and MEF2C transcriptional activity which contributes to SM atrophy in CC models.
| S-EPMC8997966 | biostudies-literature
Project description:BackgroundSarcopenia is common in patients with Parkinson's disease (PD), showing mitochondrial oxidative stress in skeletal muscle. The aggregation of α-synuclein (α-Syn) to induce oxidative stress is a key pathogenic process of PD; nevertheless, we know little about its potential role in regulating peripheral nerves and the function of the muscles they innervate.MethodsTo investigate the role of α-Syn aggregation on neuromuscular system, we used the Thy1 promoter to overexpress human α-Syn transgenic mice (mThy1-hSNCA). hα-Syn expression was evaluated by western blot, and its localization was determined by confocal microscopy. The impact of α-Syn aggregation on the structure and function of skeletal muscle mitochondria and neuromuscular junctions (NMJs), as well as muscle mass and function were characterized by flow cytometry, transmission electron microscopy, Seahorse XF24 metabolic assay, and AAV9 in vivo injection. We assessed the regenerative effect of mitochondrial-targeted superoxide dismutase (Mito-TEMPO) after skeletal muscle injury in mThy1-hSNCA mice.ResultsOverexpressed hα-Syn protein localized in motor neuron axons and NMJs in muscle and formed aggregates. α-Syn aggregation increased the number of abnormal mitochondrial in the intramuscular axons and NMJs by over 60% (P < 0.01), which inhibited the release of acetylcholine (ACh) from presynaptic vesicles in NMJs (P < 0.05). The expression of genes associated with NMJ activity, neurotransmission and regulation of reactive oxygen species (ROS) metabolic process were significantly decreased in mThy1-hSNCA mice, resulting in ROS production elevated by ~220% (P < 0.05), thereby exacerbating oxidative stress. Such process altered mitochondrial spatial relationships to sarcomeric structures, decreased Z-line spacing by 36% (P < 0.05) and increased myofibre apoptosis by ~10% (P < 0.05). Overexpression of α-Syn altered the metabolic profile of muscle satellite cells (MuSCs), including basal respiratory capacity (~170% reduction) and glycolytic capacity (~150% reduction) (P < 0.05) and decreased cell migration and fusion during muscle regeneration (~60% and ~40%, respectively) (P < 0.05). We demonstrated that Mito-TEMPO treatment could restore the oxidative stress status (the complex I/V protein and enzyme activities increased ~200% and ~150%, respectively), which caused by α-Syn aggregation, and improve the ability of muscle regeneration after injury. In addition, the NMJ receptor fragmentation and ACh secretion were also improved.ConclusionsThese results reveal that the α-synuclein aggregation plays an important role in regulating acetylcholine release from neuromuscular junctions and induces intramuscular mitochondrial oxidative stress, which can provide new insights into the aetiology of muscle atrophy in patients with Parkinson's disease.
| S-EPMC9891985 | biostudies-literature
Project description:Mixed reports exist about the role of 25-hydroxyvitamin D (25(OH)D) in muscle ageing and there are few prospective studies involving the very old (aged ? 85) who are at highest risk of low 25(OH)D, loss of muscle mass and strength, and physical performance decline. In the Newcastle 85+ Study (n = 845), we aimed to determine the association between 25(OH)D season-specific quartiles (hereafter SQ1-SQ4), grip strength (GS) and physical performance decline (Timed Up-and-Go Test, TUG) over 5 years using mixed models. In the time-only models with linear and quadratic slopes, SQ1 and SQ4 of 25(OH)D were associated with weaker GS initially in men (SQ1: ? (SE) = -2.56 (0.96); SQ4: -2.16 (1.06)) and women (SQ1: -1.10 (0.52); SQ4: -1.28 (0.50)) (all p ? 0.04). In the fully adjusted models, only men in SQ1 had a significant annual decline in GS of 1.41 kg which accelerated over time (-0.40 (0.1)), (both p ? 0.003) compared with those in combined middle quartiles. Only women in SQ1 and SQ4 of 25(OH)D had worse TUG times initially, but the rate of TUG decline was not affected. Low baseline 25(OH)D may contribute to muscle strength decline in the very old and particularly in men.
| S-EPMC5409718 | biostudies-literature
Project description:Exercise training improves muscle fitness in many aspects, including induction of mitochondrial biogenesis and maintenance of mitochondrial dynamics. The insulin-like growth factors were recently proposed as key regulators of myogenic factors to regulate muscle development. The present study aimed to investigate the physical exercise impact on insulin-like growth factor 2 (IGF2) and analyzed its functions on skeletal muscle cells in vitro. Using online databases, we stated that IGF2 was relatively highly expressed in skeletal muscle cells and increased after exercise training. Then, IGF2 deficiency in myotubes from C2C12 and primary skeletal muscle cells (PMSCs) led to impaired mitochondrial function, reduced mitochondria-related protein content, and decreased mitochondrial biogenesis. Furthermore, we explored the possible regulatory pathway and found that mitochondrial regulation in skeletal muscle cells might occur through IGF2-Sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) signaling pathway. Therefore, the present study first demonstrated the relationship between IGF2 and mitochondria in skeletal muscle.
| S-EPMC8055961 | biostudies-literature
Project description:BackgroundAlthough vitamin D is well known for its function in calcium homeostasis and bone mineralization, several studies have shown positive effects on muscle strength and physical function. In addition, vitamin D has been associated with pulmonary function and the incidence of airway infections. As vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients, supplementation might have a beneficial effect in these patients.ObjectiveTo assess the effect of vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients. Secondary outcomes are pulmonary function, handgrip strength, exacerbation rate, and quality of life.MethodsWe performed a randomized, double-blind, placebo-controlled pilot trial. Participants were randomly allocated to receive 1,200 IU vitamin D3 per day (n=24) or placebo (n=26) during 6 months. Study visits were conducted at baseline, and at 3 and 6 months after randomization. During the visits, blood was collected, respiratory muscle strength was measured (maximum inspiratory and expiratory pressure), physical performance and 6-minute walking tests were performed, and handgrip strength and pulmonary function were assessed. In addition, participants kept a diary card in which they registered respiratory symptoms.ResultsAt baseline, the mean (standard deviation [SD]) serum 25-hydroxyvitamin D (25(OH)D) concentration (nmol/L) was 42.3 (15.2) in the vitamin D group and 40.6 (17.0) in the placebo group. Participants with vitamin D supplementation had a larger increase in serum 25(OH)D compared to the placebo group after 6 months (mean difference (SD): +52.8 (29.8) vs +12.3 (25.1), P<0.001). Primary outcomes, respiratory muscle strength and physical performance, did not differ between the groups after 6 months. In addition, no differences were found in the 6-minute walking test results, handgrip strength, pulmonary function, exacerbation rate, or quality of life.ConclusionVitamin D supplementation did not affect (respiratory) muscle strength or physical performance in this pilot trial in vitamin D-deficient COPD patients.
| S-EPMC5584776 | biostudies-literature