Shin Fujimaki

Wnt Protein-mediated Satellite Cell Conversion in Adult and Aged Mice Following Voluntary Wheel Running

Background: Satellite cells are activated in response to muscle injury or mechanical stimuli. Results: Running-induced up-regulation of Wnt/β-catenin signaling activates Myf5 and MyoD transcription. Conclusion: Voluntary wheel running induces satellite cell activation by direct regulation of Wnt/β-catenin signaling. Significance: Focusing on Wnt signaling may help to understand the function and intrinsic ability of satellite cells in adult myogenesis. Muscle represents an abundant, accessible, and replenishable source of adult stem cells. Skeletal muscle-derived stem cells, called satellite cells, play essential roles in regeneration after muscle injury in adult skeletal muscle. Although the molecular mechanism of muscle regeneration process after an injury has been extensively investigated, the regulation of satellite cells under steady state during the adult stage, including the reaction to exercise stimuli, is relatively unknown. Here, we show that voluntary wheel running exercise, which is a low stress exercise, converts satellite cells to the activated state due to accelerated Wnt signaling. Our analysis showed that up-regulated canonical Wnt/β-catenin signaling directly modulated chromatin structures of both MyoD and Myf5 genes, resulting in increases in the mRNA expression of Myf5 and MyoD and the number of proliferative Pax7+Myf5+ and Pax7+ MyoD+ cells in skeletal muscle. The effect of Wnt signaling on the activation of satellite cells, rather than Wnt-mediated fibrosis, was observed in both adult and aged mice. The association of β-catenin, T-cell factor, and lymphoid enhancer transcription factors of multiple T-cell factor/lymphoid enhancer factor regulatory elements, conserved in mouse, rat, and human species, with the promoters of both the Myf5 and MyoD genes drives the de novo myogenesis in satellite cells even in aged muscle. These results indicate that exercise-stimulated extracellular Wnts play a critical role in the regulation of satellite cells in adult and aged skeletal muscle.

MicroRNAs and epigenetics in adult neurogenesis.

Neurogenesis occurs throughout adulthood in the mammalian brain. Neural stem cells (NSCs) exist in three distinct areas of the brain: the subventricular zone, the olfactory bulb, and the dentate gyrus of the hippocampus. MicroRNAs (miRNAs) are small noncoding RNA molecules that posttranscriptionally regulate gene expression. Epigenetic regulation of gene expression, which includes DNA methylation and histone modification, plays a significant role in modulating NSC proliferation and differentiation. However, the functions of miRNAs in neurogenesis are just beginning to be understood. Based on the recent literature, miRNAs are suggested to play an important role in the epigenetic regulation of NSCs and differentiation of lineage populations, which include neurons, astrocytes, and oligodendrocytes. Recent studies have elucidated the roles of miRNAs in embryonic and adult neurogenesis, specifically, their involvement in stem cell maintenance and differentiation, neuronal maturation and neurite outgrowth, dendritogenesis, and spine formation. The cross-talk between miRNAs and epigenetic regulators appears to modulate neurogenesis in the adult mammalian brain. Since the dysfunction in miRNA machinery contributes to many types of neurodegenerative disorders, a better understanding of how miRNAs influence the neurogenesis and differentiation may offer novel targets for therapeutic application.

Diabetes and Stem Cell Function

Diabetes mellitus is one of the most common serious metabolic diseases that results in hyperglycemia due to defects of insulin secretion or insulin action or both. The present review focuses on the alterations to the diabetic neuronal tissues and skeletal muscle, including stem cells in both tissues, and the preventive effects of physical activity on diabetes. Diabetes is associated with various nervous disorders, such as cognitive deficits, depression, and Alzheimers disease, and that may be caused by neural stem cell dysfunction. Additionally, diabetes induces skeletal muscle atrophy, the impairment of energy metabolism, and muscle weakness. Similar to neural stem cells, the proliferation and differentiation are attenuated in skeletal muscle stem cells, termed satellite cells. However, physical activity is very useful for preventing the diabetic alteration to the neuronal tissues and skeletal muscle. Physical activity improves neurogenic capacity of neural stem cells and the proliferative and differentiative abilities of satellite cells. The present review proposes physical activity as a useful measure for the patients in diabetes to improve the physiological functions and to maintain their quality of life. It further discusses the use of stem cell-based approaches in the context of diabetes treatment.

Intrinsic ability of adult stem cell in skeletal muscle: an effective and replenishable resource to the establishment of pluripotent stem cells.

Adult stem cells play an essential role in mammalian organ maintenance and repair throughout adulthood since they ensure that organs retain their ability to regenerate. The choice of cell fate by adult stem cells for cellular proliferation, self-renewal, and differentiation into multiple lineages is critically important for the homeostasis and biological function of individual organs. Responses of stem cells to stress, injury, or environmental change are precisely regulated by intercellular and intracellular signaling networks, and these molecular events cooperatively define the ability of stem cell throughout life. Skeletal muscle tissue represents an abundant, accessible, and replenishable source of adult stem cells. Skeletal muscle contains myogenic satellite cells and muscle-derived stem cells that retain multipotent differentiation abilities. These stem cell populations have the capacity for long-term proliferation and high self-renewal. The molecular mechanisms associated with deficits in skeletal muscle and stem cell function have been extensively studied. Muscle-derived stem cells are an obvious, readily available cell resource that offers promise for cell-based therapy and various applications in the field of tissue engineering. This review describes the strategies commonly used to identify and functionally characterize adult stem cells, focusing especially on satellite cells, and discusses their potential applications.

The regulation of stem cell aging by Wnt signaling.

Aging is an inevitable physiological process that leads to the dysfunction of various tissues, and these changes may contribute to certain diseases, and ultimately death. Recent research has discovered biological pathways that promote aging. This review focuses on Wnt signaling, Wnt is a highly conserved secreted signaling molecule that plays an essential role in the development and function of various tissues, and is a notable factor that regulates aging. Although Wnt signaling influences aging in various tissues, its effects are particularly prominent in neuronal tissue and skeletal muscle. In neuronal tissue, neurogenesis is attenuated by the downregulation of Wnt signaling with aging. Skeletal muscle can also become weaker with aging, in a process known as sarcopenia. A notable cause of sarcopenia is the myogenic-to-fibrogenic trans-differentiation of satellite cells by excessive upregulation of Wnt signaling with aging, resulting in the impaired regenerative capacity of aged skeletal muscle. However, exercise is very useful for preventing the age-related alterations in neuronal tissue and skeletal muscle. Upregulation of Wnt signaling is implicated in the positive effects of exercise, resulting in the activation of neurogenesis in adult neuronal tissue and myogenesis in mature skeletal muscle. Although more investigations are required to thoroughly understand age-related changes and their biological mechanisms in a variety of tissues, this review proposes exercise as a useful therapy for the elderly, to prevent the negative effects of aging and maintain their quality of life.

The insulin regulatory network in adult hippocampus and pancreatic endocrine system.

There is a very strong correlation between the insulin-mediated regulatory system of the central nervous system and the pancreatic endocrine system. There are many examples of the same transcriptional factors being expressed in both regions in their embryonic development stages. Hormonal signals from the pancreatic islets influence the regulation of energy homeostasis by the brain, and the brain in turn influences the secretions of the islets. Diabetes induces neuronal death in different regions of the brain especially hippocampus, causes alterations on the neuronal circuits and therefore impairs learning and memory, for which the hippocampus is responsible. The hippocampus is a region of the brain where steady neurogenesis continues throughout life. Adult neurogenesis from undifferentiated neural stem cells is greatly decreased in diabetic patients, and as a result their learning and memory functions decline. Might it be possible to reactivate stem cells whose functions have deteriorated and that are present in the tissues in which the lesions occur in diabetes, a lifestyle disease, which plagues modern humans and develops as a result of the behavior of insulin-related factor? In this paper we summarize research in regard to these matters based on examples in recent years.

Functional Overload Enhances Satellite Cell Properties in Skeletal Muscle

Skeletal muscle represents a plentiful and accessible source of adult stem cells. Skeletal-muscle-derived stem cells, termed satellite cells, play essential roles in postnatal growth, maintenance, repair, and regeneration of skeletal muscle. Although it is well known that the number of satellite cells increases following physical exercise, functional alterations in satellite cells such as proliferative capacity and differentiation efficiency following exercise and their molecular mechanisms remain unclear. Here, we found that functional overload, which is widely used to model resistance exercise, causes skeletal muscle hypertrophy and converts satellite cells from quiescent state to activated state. Our analysis showed that functional overload induces the expression of MyoD in satellite cells and enhances the proliferative capacity and differentiation potential of these cells. The changes in satellite cell properties coincided with the inactivation of Notch signaling and the activation of Wnt signaling and likely involve modulation by transcription factors of the Sox family. These results indicate the effects of resistance exercise on the regulation of satellite cells and provide insight into the molecular mechanism of satellite cell activation following physical exercise.

Nrf2 deficiency does not affect denervation‐induced alterations in mitochondrial fission and fusion proteins in skeletal muscle

Oxidative stress‐induced mitochondrial dysfunction is associated with age‐related and disuse‐induced skeletal muscle atrophy. However, the role of nuclear factor erythroid 2‐related factor 2 (Nrf2) during muscle fiber atrophy remains to be elucidated. In this study, we examined whether deficiency of Nrf2, a master regulator of antioxidant transcription, promotes denervation‐induced mitochondrial fragmentation and muscle atrophy. We found that the expression of Nrf2 and its target antioxidant genes was upregulated at 2 weeks after denervation in wild‐type (WT) mice. The response of these antioxidant genes was attenuated in Nrf2 knockout (KO) mice. Nrf2 KO mice exhibited elevated levels of 4‐hydroxynonenal in the skeletal muscle, whereas the protein levels of the mitochondrial oxidative phosphorylation complex IV was declined in the denervated muscle of these mice. Increased in mitochondrial fission regulatory proteins and decreased fusion proteins in response to denervation were observed in both WT and KO mice; however, no difference was observed between the two groups. These findings suggest that Nrf2 deficiency aggravates denervation‐induced oxidative stress, but does not affect the alterations in mitochondrial morphology proteins and the loss of skeletal muscle mass.

Diabetes-Induced Dysfunction of Mitochondria and Stem Cells in Skeletal Muscle and the Nervous System.

Diabetes mellitus is one of the most common metabolic diseases spread all over the world, which results in hyperglycemia caused by the breakdown of insulin secretion or insulin action or both. Diabetes has been reported to disrupt the functions and dynamics of mitochondria, which play a fundamental role in regulating metabolic pathways and are crucial to maintain appropriate energy balance. Similar to mitochondria, the functions and the abilities of stem cells are attenuated under diabetic condition in several tissues. In recent years, several studies have suggested that the regulation of mitochondria functions and dynamics is critical for the precise differentiation of stem cells. Importantly, physical exercise is very useful for preventing the diabetic alteration by improving the functions of both mitochondria and stem cells. In the present review, we provide an overview of the diabetic alterations of mitochondria and stem cells and the preventive effects of physical exercise on diabetes, focused on skeletal muscle and the nervous system. We propose physical exercise as a countermeasure for the dysfunction of mitochondria and stem cells in several target tissues under diabetes complication and to improve the physiological function of patients with diabetes, resulting in their quality of life being maintained.

Monitoring neurodegeneration in diabetes using adult neural stem cells derived from the olfactory bulb

IntroductionNeurons have the intrinsic capacity to produce insulin, similar to pancreatic cells. Adult neural stem cells (NSCs), which give rise to functional neurons, can be established and cultured not only by intracerebral collection, which requires difficult surgery, but also by collection from the olfactory bulb (OB), which is relatively easy. Adult neurogenesis in the hippocampus (HPC) is significantly decreased in diabetes patients. As a result, learning and memory functions, for which the HPC is responsible, decrease.MethodsIn the present study, we compared the effect of diabetes on neurogenesis and insulin expression in adult NSCs. Adult NSCs were derived from the HPC or OB of streptozotocin-induced diabetic rats. Comparative gene-expression analyses were carried out by using extracted tissues and established adult NSC cultures from the HPC or OB in diabetic rats.ResultsDiabetes progression influenced important genes that were required for insulin expression in both OB- and HPC-derived cells. Additionally, we found that the expression levels of several genes, such as voltage-gated sodium channels, glutamate transporters, and glutamate receptors, were significantly different in OB and HPC cells collected from diabetic rats.ConclusionsBy using identified diabetes-response genes, OB NSCs from diabetes patients can be used during diabetes progression to monitor processes that cause neurodegeneration in the central nervous system (CNS). Because hippocampal NSCs and OB NSCs exhibited similar gene-expression profiles during diabetes progression, OB NSCs, which are more easily collected and established than HPC NSCs, may potentially be used for screening of effective drugs for neurodegenerative disorders that cause malignant damage to CNS functions.