Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to be a negative regulator of myogenesis. Here we show that myostatin functions by controlling the proliferation of muscle precursor cells. When C2C12 myoblasts were incubated with myostatin, proliferation of myoblasts decreased with increasing levels of myostatin. Fluorescence-activated cell sorting analysis revealed that myostatin prevented the progression of myoblasts from the G1- to S-phase of the cell cycle. Western analysis indicated that myostatin specifically up-regulated p21Waf1, Cip1, a cyclin-dependent kinase inhibitor, and decreased the levels and activity of Cdk2 protein in myoblasts. Furthermore, we also observed that in myoblasts treated with myostatin protein, Rb was predominately present in the hypophosphorylated form. These results suggests that, in response to myostatin signaling, there is an increase in p21 expression and a decrease in Cdk2 protein and activity thus resulting in an accumulation of hypophosphorylated Rb protein. This, in turn, leads to the arrest of myoblasts in G1-phase of cell cycle. Thus, we propose that the generalized muscular hyperplasia phenotype observed in animals that lack functional myostatin could be as a result of deregulated myoblast proliferation.

Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation.

To date, studies suggest that biological signaling by nitric oxide (NO) is primarily mediated by cGMP, which is synthesized by NO-activated guanylyl cyclases and broken down by cyclic nucleotide phosphodiesterases (PDEs). Effects of cGMP occur through three main groups of cellular targets: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and PDEs. cGMP binding activates PKG, which phosphorylates serines and threonines on many cellular proteins, frequently resulting in changes in activity or function, subcellular localization, or regulatory features. The proteins that are so modified by PKG commonly regulate calcium homeostasis, calcium sensitivity of cellular proteins, platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes. Current therapies that have successfully targeted the NO-signaling pathway include nitrovasodilators (nitroglycerin), PDE5 inhibitors [sildenafil (Viagra and Revatio), vardenafil (Levitra), and tadalafil (Cialis and Adcirca)] for treatment of a number of vascular diseases including angina pectoris, erectile dysfunction, and pulmonary hypertension; the PDE3 inhibitors [cilostazol (Pletal) and milrinone (Primacor)] are used for treatment of intermittent claudication and acute heart failure, respectively. Potential for use of these medications in the treatment of other maladies continues to emerge.

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

As a chemical transmitter in the mammalian central nervous system, nitric oxide (NO) is still thought a bit of an oddity, yet this role extends back to the beginnings of the evolution of the nervous system, predating many of the more familiar neurotransmitters. During the 20 years since it became known, evidence has accumulated for NO subserving an increasing number of functions in the mammalian central nervous system, as anticipated from the wide distribution of its synthetic and signal transduction machinery within it. This review attempts to probe beneath those functions and consider the cellular and molecular mechanisms through which NO evokes short- and long-term modifications in neural performance. With any transmitter, understanding its receptors is vital for decoding the language of communication. The receptor proteins specialised to detect NO are coupled to cGMP formation and provide an astonishing degree of amplification of even brief, low amplitude NO signals. Emphasis is given to the diverse ways in which NO receptor activation initiates changes in neuronal excitability and synaptic strength by acting at pre- and/or postsynaptic locations. Signalling to non-neuronal cells and an unexpected line of communication between endothelial cells and brain cells are also covered. Viewed from a mechanistic perspective, NO conforms to many of the rules governing more conventional neurotransmission, particularly of the metabotropic type, but stands out as being more economical and versatile, attributes that presumably account for its spectacular evolutionary success.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1460-9568.2008.06285.x

Concepts of neural nitric oxide‐mediated transmission

Determinants of masticatory performance in dentate adults

Nitric oxide (NO) is an important signaling molecule that is widely used in the nervous system. With recognition of its roles in synaptic plasticity (long-term potentiation, LTP; long-term depression, LTD) and elucidation of calcium-dependent, NMDAR-mediated activation of neuronal nitric oxide synthase (nNOS), numerous molecular and pharmacological tools have been used to explore the physiology and pathological consequences for nitrergic signaling. In this review, the authors summarize the current understanding of this subtle signaling pathway, discuss the evidence for nitrergic modulation of ion channels and homeostatic modulation of intrinsic excitability, and speculate about the pathological consequences of spillover between different nitrergic compartments in contributing to aberrant signaling in neurodegenerative disorders. Accumulating evidence points to various ion channels and particularly voltage-gated potassium channels as signaling targets, whereby NO mediates activity-dependent control of intrinsic neuronal excitability; such changes could underlie broader mechanisms of synaptic plasticity across neuronal networks. In addition, the inability to constrain NO diffusion suggests that spillover from endothelium (eNOS) and/or immune compartments (iNOS) into the nervous system provides potential pathological sources of NO and where control failure in these other systems could have broader neurological implications. Abnormal NO signaling could therefore contribute to a variety of neurodegenerative pathologies such as stroke/excitotoxicity, Alzheimer's disease, multiple sclerosis, and Parkinson's disease.

Nitric Oxide Signaling in Brain Function, Dysfunction, and Dementia

The relationship between the height of the mandibular residual ridge and the severity of osteoporosis in elderly edentulous patients was investigated. The height of the mandibular residual ridge was measured by use of the mental foramen on panoramic radiographs. The severity of osteoporosis was determined by examining frontal and lateral radiographs of the vertebrae. All of the patients received a blood analysis. The correlation coefficient between age and the height of residual ridge was -0.38, which was statistically significant (p < 0.01). The residual ridge in women was lower than that of men, showing a statistical significance (p < 0.01). The correlation coefficient was -0.42 between degree of severity of osteoporosis and the height of the residual ridge, which was significant (p < 0.01). The parathyroid hormone level was high in the patients with a low residual ridge, and the calcitonin (CT) level was low. This study indicates that osteoporosis strongly affects reduction of the residual ridge in edentulous patients.

Osteoporosis and reduction of residual ridge in edentulous patients.

Statement of Problem. For complete denture wearers the tongue plays an important role in the retention and stability of dentures and has a great influence on masticatory function. Purpose of Study. The purpose of this study was to elucidate the relationship between tongue motor behavior and masticatory function. Material and Methods. Thirty healthy, normal adult dentates, 10 normal elderly dentates, and 20 complete denture wearers whose dentures were constructed by the same methods and materials were selected. Tongue motor skills were examined by an ultrasound system and masticatory performance was evaluated by the sieving method. Results. The tongue motor skills of elderly dentates and complete denture wearers were statistically lower compared with those of adult dentates ( p p p p Conclusion. Age-related decreases in tongue motor skills and masticatory performance were demonstrated by ultrasound observations and sieving methods. (J Prosthet Dent 1997;77:147-52.)

Tongue motor skills and masticatory performance in adult dentates, elderly dentates, and complete denture wearers.

Age-related changes in masticatory function were investigated in complete denture wearers. The sieving method using peanuts as a test food was compared with the result obtained using a food questionnaire for evaluation of masticatory function. In relationship to aging, both the masticatory performance and the chewing score decreased significantly (the masticatory performance: r = .60, P < .01; the mastication score: r = -.46, P < .05). It is suggested that the masticatory function in complete denture wearers decreases in relationship to aging. The food intake questionnaire is useful for evaluating masticatory function in complete denture wearers.

Age-related change of masticatory function in complete denture wearers: evaluation by a sieving method with peanuts and a food intake questionnaire method.

In order to examine the relationship between occlusal support and head posture, the electromyographic (EMG) activities of the jaw closing muscles and the sternocleidomastoid muscle during voluntary maximal clenching (VMC) under several conditions of occlusal support in eight healthy dentates were recorded and analysed. The head posture was also recorded simultaneously by the electromagnetic, 6-degree-of-freedom tracking instrument (POLHMUS Co. 3 SPACE-WIN*). In the VMC with lateral imbalance of occlusal support, EMG activity of the jaw closing muscles and the sternocleidomastoid muscle on the occlusal support side was greater than those on the non-occlusal support side, and the neck was bent in the direction of the occlusal support side. Moreover, a positive correlation was found between the asymmetry of muscle activity (asymmetry index) of the sternocleidomastoid muscle and the angle of lateral bending of the neck. From these results, it can be said that lateral imbalance of the occlusal support could promote imbalance in sternocleidomastoid muscle activity, causing lateral bending of the neck. From this study, it is suggested that there is a close relationship between occlusal support and head posture.

Occlusal support and head posture

Successful prosthodontic treatments for a patient with removable partial dentures including maxillofacial prostheses hopefully brings about psychological wellbeing as well as improved health. The purpose of this study was to investigate the relationship between quality of life (QOL) and the various aspects of denture function. At first, a questionnaire with a visual analog scale with 16 question items concerning denture and/or eating problems, the present state of health, psychological and physical wellbeing, life satisfaction, and QOL was developed. To discuss the validity and reliability of the questionnaire, 48 outpatients who wore a denture were asked to fill it out. Next, to discuss the difference in QOL of the patient with various kinds of dentures and conditions, 103 outpatients were asked to complete the newly developed questionnaire. The questionnaire which contained four factor areas with eight questions for denture patients was developed by factor analysis with Varimax rotation. The reliability of the QOL scale was confirmed by reliability analysis (Cronbach's alpha = 0.784). The QOL score of edentulous patients with a complete denture having some trouble chewing was significantly lower than that of other denture patients. It was suggested that the wearing of a denture significantly affected the QOL of elderly persons.

Toshihiro Hirai

Papers

Osteoporosis and reduction of residual ridge in edentulous patients.

Tongue motor skills and masticatory performance in adult dentates, elderly dentates, and complete denture wearers.

Age-related change of masticatory function in complete denture wearers: evaluation by a sieving method with peanuts and a food intake questionnaire method.

Occlusal support and head posture

Quality of life and masticatory function in denture wearers.