Role of thyroid hormones in early postnatal development of skeletal muscle and its implications for undernutrition

Published online by Cambridge University Press 09 Mar 2007Energy intake profoundly influences many endocrine axes which in turn play a central role in development. The specific influence of a short period of mild hypothyroidism, similar to that induced by undernutrition, in regulating muscle development has been assessed in a large mammal during early postnatal life. Hypothyroidism was induced by providing methimazole and iopanoic acid in the feed of piglets between 4 and 14 d of age, and controls were pair-fed to the energy intake of their hypothyroid littermates. Thyroid status was evaluated, and myofibre differentiation and cation pump concentrations were then assessed in the following functionally distinct muscles: longissimus dorsi (l. dorsi), soleus and rhomboideus. Reductions in plasma concentrations of thyroxine (T4; 32%, P < O·Ol), triiodothyronine (T3;48%, P < 0·001), free T3, (58%, P < 0·001)and hepatic 5'-monodeiodinase (EC 1.11.1.8) activity (74%, P < 0·001) occurred with treatment. Small, although significant, increases in the proportion of type I slow-twitch oxidative fibres occurred with mild hypothyroidism, in l. dorsi (2%, P < 0·01) and soleus(7%, P < 0·01). Nuclear T3-receptor concentration in l. dorsi of hypothyroid animals compared with controls increased by 46% (P < 0·001), a response that may represent a homeostatic mechanism making muscle more sensitive to low levels of circulating thyroid hormones. Nevertheless, Na+, K+-ATPase (EC 3.6.1.37) concentration was reduced by 15–16% in all muscles (l.dorsi P< 0·05,soleus P < 0·001, rhomboideus P < 0·05), and Ca2+-ATPase (EC 3.6.1.38) concentration was significantly reduced in the two slow-twitch muscles: by 22% in rhomboideus (P < 0·001) and 23% in soleus (P < 0·05). It is concluded that during early postnatal development of large mammals a period of mild hypothyroidism, comparable with that found during undernutrition, induces changes in myofibre differentiation and a down-regulation of cation pumps in skeletal muscle. Such changes would result in slowness of movement and muscle weakness, and also reduce ATP hydrolysis with a concomitant improvement in energetic efficiency.A. P. Harrison, D. R. Tivey, T. Clausen, C. Duchamp and M. J. Daunce

The ER-Bound RING Finger Protein 5 (RNF5/RMA1) Causes Degenerative Myopathy in Transgenic Mice and Is Deregulated in Inclusion Body Myositis

Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of β-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders

Absence of CD34 on Murine Skeletal Muscle Satellite Cells Marks a Reversible State of Activation during Acute Injury

Background: Skeletal muscle satellite cells are myogenic progenitors that reside on myofiber surface beneath the basal lamina. In recent years satellite cells have been identified and isolated based on their expression of CD34, a sialomucin surface receptor traditionally used as a marker of hematopoietic stem cells. Interestingly, a minority of satellite cells lacking CD34 has been described. Methodology/Principal Findings: In order to elucidate the relationship between CD34+ and CD34- satellite cells we utilized fluorescence-activated cell sorting (FACS) to isolate each population for molecular analysis, culture and transplantation studies. Here we show that unless used in combination with a7 integrin, CD34 alone is inadequate for purifying satellite cells. Furthermore, the absence of CD34 marks a reversible state of activation dependent on muscle injury. Conclusions/Significance: Following acute injury CD34- cells become the major myogenic population whereas the percentage of CD34+ cells remains constant. In turn activated CD34- cells can reverse their activation to maintain the pool of CD34+ reserve cells. Such activation switching and maintenance of reserve pool suggests the satellite cell compartment is tightly regulated during muscle regeneration

A predictive speller controlled by a brain-computer interface based on motor imagery

reserved5Persons suffering from motor disorders have limited possibilities for communicating and normally require assistive technologies to fulfill this primary need. Promising means of providing basic communication abilities to subjects affected by severe motor impairments include brain-computer interfaces (BCIs), that is, systems that directly translate brain signals into device commands, bypassing any muscle or nerve mediation. To date, the use of BCIs for effective verbal communication is yet an open issue, primarily due to the low rates of information transfer that can be achieved with this technology. Still, performance of BCI spelling applications could be considerably improved by a smart user interface design and by the adoption of natural language processing (NLP) techniques for text prediction. The objective of this work is to suggest an approach and a user interface for BCI spelling applications combining state-of-the-art BCI and NLP techniques to maximize the overall communication rate of the system. The BCI paradigm adopted is motor imagery, that is, when the subject imagines moving a certain part of the body, he/she produces modifications to specific brain rhythms that are detected in real-time through an electroencephalogram and translated into commands for a spelling application. By maximizing the overall communication rate, our approach is twofold: on one hand, we maximize the information transfer rate from the control signal, on the other hand, we optimize the way this information is employed for the purpose of verbal communication. The achieved results are satisfactory and comparable with the latest works reported in literature on motor-imagery BCI spellers. For the three subjects tested, we obtained a spelling rate of respectively 3 char/min, 2.7 char/min, and 2 char/min.T. D'Albis; R. Blatt; R. Tedesco; L. Sbattella; M. Matteucci;T., D'Albis; R., Blatt; Tedesco, Roberto; Sbattella, Licia; Matteucci, Matte

Recurrent amplification of grid‐cell activity

High-level cognitive abilities such as navigation and spatial memory are thought to rely on the activity of grid cells in the medial entorhinal cortex (MEC), which encode the animal's position in space with periodic triangular patterns. Yet the neural mechanisms that underlie grid-cell activity are still unknown. Recent in vitro and in vivo experiments indicate that grid cells are embedded in highly structured recurrent networks. But how could recurrent connectivity become structured during development? And what is the functional role of these connections? With mathematical modeling and simulations, we show that recurrent circuits in the MEC could emerge under the supervision of weakly grid-tuned feedforward inputs. We demonstrate that a learned excitatory connectivity could amplify grid patterns when the feedforward sensory inputs are available and sustain attractor states when the sensory cues are lost. Finally, we propose a Fourier-based measure to quantify the spatial periodicity of grid patterns: the grid-tuning index.Peer Reviewe