scholarly journals Creatine transporter deficient rat show motor dysfunction linked with cerebellar alterations and muscle creatine deficiency without muscle atrophy

2021 ◽  
Author(s):  
Lara Duran-Trio ◽  
Gabriella Fernandes-Pires ◽  
Jocelyn Grosse ◽  
Ines Soro-Arnaiz ◽  
Clothilde Roux-Petronelli ◽  
...  
Keyword(s):  
Motor Function ◽  
Muscle Atrophy ◽  
Motor Dysfunction ◽  
Loss Of Function ◽  
Efficient Treatment ◽  
Morphological Alterations ◽  
Genes Encoding ◽  
Creatine Deficiency ◽  
Transporter Deficiency ◽  
And Performance

Creatine (Cr) is a nitrogenous organic acid and plays roles as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy and motor dysfunction. Among CCDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8Y389C knock-in (KI) rat model of CTD showed mild impaired motor function linked with morphological alterations in cerebellum, reduced muscular mass, Cr deficiency and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction is due to both nervous and muscle dysfunction, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain.

scholarly journals A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

2020 ◽  
Author(s):  
Lara Duran-Trio ◽  
Gabriella Fernandes-Pires ◽  
Dunja Simicic ◽  
Jocelyn Grosse ◽  
Clothilde Roux ◽  
...  
Keyword(s):  
Point Mutation ◽  
Rat Model ◽  
Energy Demand ◽  
High Energy ◽  
Behavioral Disorder ◽  
Creatine Transporter ◽  
Efficient Treatment ◽  
Creatine Transporter Deficiency ◽  
Creatine Deficiency ◽  
Transporter Deficiency

ABSTRACTCreatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficiency and autistic features. Slc6a8xY389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

scholarly journals Saikokeishikankyoto extract alleviates muscle atrophy in KKAy mice

2022 ◽  
Author(s):  
Yanglan Ou ◽  
Kohei Jobu ◽  
Tomoaki Ishida ◽  
Shumpei Morisawa ◽  
Hiroko Fujita ◽  
...  
Keyword(s):  
Motor Function ◽  
Muscle Atrophy ◽  
Transcriptional Activity ◽  
Hot Water ◽  
Motor Dysfunction ◽  
Sirtuin 1 ◽  
Sarcopenic Obesity ◽  
Skeletal Muscle Atrophy ◽  
Kkay Mice

AbstractSarcopenic obesity is associated with increased visceral fat and decreased muscle mass, resulting in decreased insulin sensitivity, increased production of inflammatory cytokines, and oxidative stress. In this study, we first evaluated the effects of herbal medicines on the transcriptional activity of the Sirtuin 1 (sirt1) promoter in vitro as an indicator of their therapeutic effect. Our data suggested that hot water Saikokeishikankyoto (SKK) extracts increased sirt1 transcriptional activity in vitro, identifying it as a candidate therapeutic for evaluation in the KKAy type 2 diabetic obesity mouse model. These in vivo evaluations revealed that SKK treatment increased the wet weight and muscle fiber content in cross sections of the gastrocnemius muscle (GA) and restored motor function in these animals. In addition, SKK treatment reduced tumor necrosis factor-α (TNFα) expression in the sera and suppressed Atrogin1 and MuRF1 transcription in the GA samples. This treatment also increased sirt1 expression in these tissues. These results suggest that SKK inhibits skeletal muscle atrophy and improves motor function in KKAy mice by suppressing inflammation. In actual clinical practice, SKK is expected to inhibit muscle atrophy and improve motor dysfunction in sarcopenic obesity. Graphical abstract

scholarly journals The Complex Flagellar Torque Generator of Pseudomonas aeruginosa

2004 ◽  
Vol 186 (19) ◽  
pp. 6341-6350 ◽  
Author(s):  
Timothy B. Doyle ◽  
Andrew C. Hawkins ◽  
Linda L. McCarter
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Membrane Proteins ◽  
Motor Function ◽  
Swimming Speed ◽  
Flagellar Motor ◽  
Loss Of Function ◽  
Wild Type ◽  
Aqueous Environments ◽  
Genes Encoding ◽  
Rotary Motors

ABSTRACT Flagella act as semirigid helical propellers that are powered by reversible rotary motors. Two membrane proteins, MotA and MotB, function as a complex that acts as the stator and generates the torque that drives rotation. The genome sequence of Pseudomonas aeruginosa PAO1 contains dual sets of motA and motB genes, PA1460-PA1461 (motAB) and PA4954-PA4953 (motCD), as well as another gene, motY (PA3526), which is known to be required for motor function in some bacteria. Here, we show that these five genes contribute to motility. Loss of function of either motAB-like locus was dispensable for translocation in aqueous environments. However, swimming could be entirely eliminated by introduction of combinations of mutations in the two motAB-encoding regions. Mutation of both genes encoding the MotA homologs or MotB homologs was sufficient to abolish motility. Mutants carrying double mutations in nonequivalent genes (i.e., motA motD or motB motC) retained motility, indicating that noncognate components can function together. motY appears to be required for motAB function. The combination of motY and motCD mutations rendered the cells nonmotile. Loss of function of motAB, motY, or motAB motY produced similar phenotypes; although the swimming speed was only reduced to ∼85% of the wild-type speed, translocation in semisolid motility agar and swarming on the surface of solidified agar were severely impeded. Thus, the flagellar motor of P. aeruginosa represents a more complex configuration than the configuration that has been studied in other bacteria, and it enables efficient movement under different circumstances.

scholarly journals A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lara Duran-Trio ◽  
Gabriella Fernandes-Pires ◽  
Dunja Simicic ◽  
Jocelyn Grosse ◽  
Clothilde Roux-Petronelli ◽  
...  
Keyword(s):  
Point Mutation ◽  
Rat Model ◽  
Energy Demand ◽  
High Energy ◽  
Behavioral Disorder ◽  
Creatine Transporter ◽  
Efficient Treatment ◽  
Creatine Transporter Deficiency ◽  
Creatine Deficiency ◽  
Transporter Deficiency

AbstractCreatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficits and autistic-like traits. The Slc6a8Y389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

scholarly journals Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

2021 ◽  
Author(s):  
Albert Misko ◽  
Laura D Weinstock ◽  
Sitara B Sankar ◽  
Amanda Furness ◽  
Yulia Grishchuk ◽  
...  
Keyword(s):  
Motor Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Loss Of Function ◽  
Brief Assessment ◽  
Blood Cytokines ◽  
Mucolipidosis Iv ◽  
Transient Receptor

Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss-of-function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. We thus hypothesized that peripheral blood cytokines would reflect inflammatory changes in the brain and would be linked to motor dysfunction. To test this, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scores. We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, IL-17, IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Like MLIV patients, IL-17 and IP-10 were up-regulated in blood of symptomatic mice. Together, our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting an importance for interferon signaling in MLIV.

scholarly journals Creatine transporter deficient rat model shows motor dysfunction, cerebellar alterations and muscle creatine deficiency without muscle atrophy

2021 ◽  
Author(s):  
Lara Duran‐Trio ◽  
Gabriella Fernandes‐Pires ◽  
Jocelyn Grosse ◽  
Ines Soro‐Arnaiz ◽  
Clothilde Roux‐Petronelli ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Rat Model ◽  
Motor Dysfunction ◽  
Creatine Transporter ◽  
Creatine Deficiency ◽  
Muscle Creatine

scholarly journals act Operon Control of Developmental Gene Expression in Myxococcus xanthus

2002 ◽  
Vol 184 (4) ◽  
pp. 1172-1179 ◽  
Author(s):  
Thomas M. A. Gronewold ◽  
Dale Kaiser
Keyword(s):  
Fruiting Body ◽  
Myxococcus Xanthus ◽  
The Other ◽  
Loss Of Function ◽  
Wild Type ◽  
Developmental Gene ◽  
Developmental Gene Expression ◽  
Mutant Strains ◽  
Genes Encoding ◽  
Signal Production

ABSTRACT Cell-bound C-signal guides the building of a fruiting body and triggers the differentiation of myxospores. Earlier work has shown that transcription of the csgA gene, which encodes the C-signal, is directed by four genes of the act operon. To see how expression of the genes encoding components of the aggregation and sporulation processes depends on C-signaling, mutants with loss-of-function mutations in each of the act genes were investigated. These mutations were found to have no effect on genes that are normally expressed up to 3 h into development and are C-signal independent. Neither the time of first expression nor the rate of expression increase was changed in actA, actB, actC, or actD mutant strains. Also, there was no effect on A-signal production, which normally starts before 3 h. By contrast, the null act mutants have striking defects in C-signal production. These mutations changed the expression of four gene reporters that are related to aggregation and sporulation and are expressed at 6 h or later in development. The actA and actB null mutations substantially decreased the expression of all these reporters. The other act null mutations caused either premature expression to wild-type levels (actC) or delayed expression (actD), which ultimately rose to wild-type levels. The pattern of effects on these reporters shows how the C-signal differentially regulates the steps that together build a fruiting body and differentiate spores within it.

scholarly journals Impairments in balance and mobility identify delirium in patients with comorbid dementia

2018 ◽  
Vol 31 (5) ◽  
pp. 749-753 ◽  
Author(s):  
Neus Gual ◽  
Sarah J. Richardson ◽  
Daniel H. J. Davis ◽  
Giuseppe Bellelli ◽  
Wolfgang Hasemann ◽  
...  
Keyword(s):  
Motor Function ◽  
Mini Mental State Examination ◽  
The Elderly ◽  
Motor Dysfunction ◽  
Cross Sectional ◽  
Dsm 5 ◽  
Hierarchical Assessment ◽  
State Examination ◽  
Rehabilitation Hospitals ◽  
Delirium Superimposed On Dementia

ABSTRACTDiagnosing delirium superimposed on dementia (DSD) remains challenging because of a lack of specific tools, though motor dysfunction in delirium has been relatively under-explored. This study aimed to use dysfunction in balance and mobility (with the Hierarchical Assessment of Balance And Mobility: HABAM) to identify DSD. This is a cross-sectional multicenter study, recruiting consecutive patients ≥70 years admitted to five acute or rehabilitation hospitals in Ireland, Italy, Portugal, and Switzerland. Delirium was diagnosed using DSM-5 criteria; dementia was determined by the Mini-Mental State Examination and the Questionnaire of Cognitive Decline in the Elderly. HABAM score was recorded at admission. Out of 114 patients (mean age ± SD = 82 ± 7; 54% female), dementia alone was present in 24.6% (n = 28), delirium alone in 18.4% (n = 21) and DSD in 27.2% (n = 31). Patients with DSD had a mean HABAM score 7 points greater than those with dementia alone (19.8 ± 8.7 vs 12.5 ± 9.5; p < 0.001); 70% of participants with DSD were correctly identified using the HABAM at a cut off of 22 (sensitivity 61%, specificity 79%, AUC = 0.76). Individuals with delirium have worse motor function than those without delirium, even in the context of comorbid dementia. Measuring motor function using the HABAM in older people at admission may help to diagnose DSD.

scholarly journals Juzentaihoto Suppresses Muscle Atrophy and Decreased Motor Function in SAMP8 Mice

2021 ◽  
Vol 44 (1) ◽  
pp. 32-38
Author(s):  
Yasuyo Morita ◽  
Tomoaki Ishida ◽  
Shumpei Morisawa ◽  
Kohei Jobu ◽  
Yangran Ou ◽  
...  
Keyword(s):  
Motor Function ◽  
Muscle Atrophy ◽  
Samp8 Mice

scholarly journals A novel mouse model of creatine transporter deficiency

F1000Research ◽  
2015 ◽  
Vol 3 ◽  
pp. 228
Author(s):  
Laura Baroncelli ◽  
Maria Grazia Alessandrì ◽  
Jonida Tola ◽  
Elena Putignano ◽  
Martina Migliore ◽  
...  
Keyword(s):  
Mouse Model ◽  
Murine Model ◽  
Deficiency Syndrome ◽  
Speech Impairment ◽  
Behavioral Disturbances ◽  
Creatine Transporter ◽  
Creatine Transporter Deficiency ◽  
Creatine Deficiency ◽  
Creatine Deficiency Syndrome ◽  
Transporter Deficiency

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement  and behavioral disturbances, language and speech impairment ( OMIM #300352).CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT−/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.

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