Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by a mutation in the dystrophin gene. In addition to muscle pathology, some patients with DMD will exhibit cognitive impairments with severity being linked to age and type of genetic mutation. Likewise, some studies have shown that mdx mice display impairments in spatial memory compared with wild‐type (WT) controls, while others have not observed any such effect. Most studies have utilized the traditional C57BL/10 (C57) mdx mouse, which exhibits a mild disease phenotype. Recently, the DBA/2J (D2) mdx mouse has emerged as a more severe and perhaps clinically relevant DMD model; however, studies examining cognitive function in these mice are limited. Thus, in this study we examined cognitive function in age‐matched C57 and D2 mdx mice along with their respective WT controls. Our findings show that 8‐ to 12‐week‐old C57 mdx mice did not display any differences in exploration time when challenged with a novel object recognition test. Conversely, age‐matched D2 mdx mice spent less time exploring objects in total as a well as less time exploring the novel object, suggestive of impaired recognition memory. Biochemical analyses of the D2 mdx brain revealed higher soluble amyloid precursor protein β (APPβ) and APP in the prefrontal cortex of mdx mice compared with WT, and lower soluble APPα in the hippocampus, suggestive of a shift towards amyloidogenesis and a similar pathogenesis to Alzheimer's disease. Furthermore, our study demonstrates the utility of the D2 mdx model in studying cognitive impairment.
The gene dosage inequality between females with two X-chromosomes and males with one is compensated for by X-chromosome inactivation (XCI), which ensures the silencing of one X in every somatic cell of female mammals. XCI in humans results in a mosaic of two cell populations: those expressing the maternal X-chromosome and those expressing the paternal X-chromosome. We have previously shown that the degree of mosaicism (the X-inactivation pattern) in a Canadian family is directly related to disease severity in female carriers of the X-linked recessive bleeding disorder, haemophilia A. The distribution of X-inactivation patterns in this family was consistent with a genetic trait having a co-dominant mode of inheritance, suggesting that XCI choice may not be completely random. To identify genetic elements that could be responsible for biased XCI choice, a linkage analysis was undertaken using an approach tailored to accommodate the continuous nature of the X-inactivation pattern phenotype in the Canadian family. Several X-linked regions were identified, one of which overlaps with a region previously found to be linked to familial skewed XCI. SA2, a component of the cohesin complex is identified as a candidate gene that could participate in XCI through its association with CTCF.
Calmodulin (CaM) is an important Ca2+-sensing protein with numerous downstream targets that are either CaM-dependant or CaM-regulated. In muscle, CaM-dependent proteins, which are critical regulators of dynamic Ca2+ handling and contractility, include calcineurin (CaN), CaM-dependant kinase II (CaMKII), ryanodine receptor (RyR), and dihydropyridine receptor (DHPR). CaM-regulated targets include genes associated with oxidative metabolism, muscle plasticity, and repair. Despite its importance in muscle, the regulation of CaM—particularly its availability to bind to and activate downstream targets—is an emerging area of research. In this minireview, we discuss recent studies revealing the importance of small IQ motif proteins that bind to CaM to either facilitate (nuclear receptor interacting protein; NRIP) its activation of downstream targets, or sequester (neurogranin, Ng; and growth-associated protein 43, GAP43) CaM away from their downstream targets. Specifically, we discuss recent studies that have begun uncovering the physiological roles of NRIP, Ng, and GAP43 in skeletal and cardiac muscle, thereby highlighting the importance of endogenously expressed CaM-binding proteins and their regulation of CaM in muscle.
This work expands the phenotypic spectrum of PFIC1, and highlights the overlap in clinical phenotype between Alagille syndrome and PFIC1. Knowledge of the causative mutation allows for carrier testing and prenatal diagnosis in this community.
Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder that leads to early mortality. We examined the pathogenic contribution of glycogen synthase kinase 3 (GSK3) to DMD using the mdx model. GSK3 is a serine/threonine kinase that has been implicated in other muscular dystrophies and our initial results showed that overactivation of GSK3 may contribute to increased disease severity found in DBA/2J (D2) mdx mice vs C57BL/10 mdx mice. In support of this, treating D2 mdx mice with the GSK3 inhibitor, tideglusib (10 mg/kg/day), increased muscle mass, strength, and fatigue resistance. We also found elevated proportions of oxidative fibers and increased utrophin mRNA, while muscle necrosis and oxidative stress were reduced. Finally, young D2 mdx mice displayed early diastolic dysfunction, and this was blunted with tideglusib treatment, an effect attributed to lowered oxidative stress and fibrosis. This study highlights the therapeutic potential of tideglusib and GSK3 inhibition for DMD.
The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump is responsible for the transport of Ca2+ from the cytosol into the sarcoplasmic reticulum at the expense of ATP, making it a regulator of both muscle relaxation and muscle-based energy expenditure. Neurogranin (Ng) is a small protein that negatively regulates calcineurin signaling. Calcineurin is Ca2+/calmodulin dependent phosphatase that promotes the oxidative fibre type in skeletal muscle and regulates muscle-based energy expenditure. A recent study has shown that calcineurin activation reduces SERCA Ca2+ transport efficiency, ultimately raising energy expenditure. Since the biomedical view of obesity states that it arises as an imbalance between energy intake and expenditure which favors the former, we questioned whether heterozygous Ng deletion (Ng+/-) would reduce SERCA efficiency and increase energy expenditure in female mice fed a high-fat diet (HFD). Young (3–4-month-old) female wild type (WT) and Ng+/- mice were fed a HFD for 12 weeks with their metabolic profile being analyzed using metabolic cages and DXA scanning, while soleus SERCA efficiency was measured using SERCA specific Ca2+ uptake and ATPase activity assays. Ng+/- mice showed significantly less cage ambulation compared to WT mice but this did not lead to any added weight gain nor changes in daily energy expenditure, glucose or insulin tolerance despite a similar level of food intake. Furthermore, we observed significant reductions in SERCA’s apparent coupling ratio which were associated with significant reductions in SERCA1 and phospholamban content. Thus, our results show that Ng regulates SERCA pump efficiency, and future studies should further investigate the potential cellular mechanisms.
Duchenne Muscular Dystrophy (DMD) is a progressive muscle wasting disorder which affects approximately 1 in 3500 male births and is caused by a mutation in the dystrophin gene. Although most research focuses on the role of dystrophin in skeletal and cardiac muscle, dystrophin is also expressed in the brain, specifically in memory‐associated brain regions like the hippocampus and cortex. Furthermore, patients with DMD and mdx mice (rodent model of DMD) exhibit significant memory and learning impairments, implicating dystrophin loss in neurodegeneration. A recent study found patients with DMD had higher serum amyloid‐β42, with this marker being heavily associated with cognitive impairments and Alzheimer's disease pathology. The purpose of this study was to characterize the neuropathology associated with DMD, focusing on markers of amyloidogenesis and synaptic function, in a preclinical mdx mouse model. Male mdx and age matched (8‐9 weeks old) wild‐type (DBA‐2J) mice were purchased from Jackson laboratories (n = 12 per group). Novel object recognition testing (NORT) was performed to determine cognitive function. Prefrontal cortex and hippocampus brain regions were extracted for analysis. NORT testing demonstrated that mdx mice had reduced exploration time of the novel object (WT 35.2 sec vs mdx 18.7 sec; p = 0.02) and a lower exploration index (‐25%, p < 0.05) compared to WT mice. Western blot analysis revealed higher soluble APP β (+40%) and total APP (+20%) in the prefrontal cortex of mdx mice compared to WT, and lower soluble APP α (‐30%) fragment in the hippocampus (p <0.05). Furthermore, PSD95 content was nearly 2‐fold higher in the prefrontal cortex of mdx mice compared to WT (p <0.05). This study provides novel information about the cellular pathways associated with memory impairment with DMD. Specifically, we show a shift towards amyloidogenesis in the prefrontal cortex and hippocampus brain regions of mdx mice, suggesting the possibility of similar pathogenesis to Alzheimer's disease. These changes are accompanied by reduced performance in the NORT test. Importantly, our results demonstrate that these changes occur at a relatively young age in D2 mdx mice, similar to what is observed in patients with DMD.
A Corrigendum onThe effects of neurogranin knockdown on SERCA pump efficiency in soleus muscles of female mice fed a high fat diet
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