Skeletal muscles, namely, postural muscles, as soleus, suffer from atrophy under disuse. Muscle atrophy development caused by unloading differs from that induced by denervation or other stimuli. Disuse atrophy is supposed to be the result of shift of protein synthesis/proteolysis balance towards protein degradation increase. Maintaining of the balance involves many systems of synthesis and proteolysis, whose activation leads to muscle adaptation to disuse rather than muscle degeneration. Here, we review recent data on activity of signaling systems involved in muscle atrophy development under unloading and muscle adaptation to the lack of support.

The recovery of the skeletal muscle structure and function after prolonged disuse is the problem of the rehabilitation and space medicine great concern. Hypokinesia affects mainly the postural muscles responsible for the support reaction. Atrophy developed under disuse is the result of the protein synthesis and proteolysis balance shift. Several signaling systems regulating proteolysis are known now, though only recently researchers paid attention to the question whether these systems work identically in the muscles atrophied under different stimuli (denervation, starvation etc.). In this review we aimed to summarize and analyze cumulative data concerning the work of the different proteolytic systems during the atrophy caused by hypokinesia and/or hypogravity. Also we discuss here the latest data about the interconnection of the signaling systems regulating the structural and functional muscle proteins degradation and synthesis under disuse.

В обзоре представлены данные об атрофии, которая вызвана длительной инактивацией скелетных мышц и представляет собой результат смещения баланса между синтезом белка и протеолизом в сторону активации распада. На сегодняшний день известно несколько сигнальных путей, участ- вующих в протеолизе, однако лишь недавно исследователи стали проявлять интерес к вопросу, ра- ботают ли эти системы одинаково при атрофии, вызванной функциональной разгрузкой и другими стимулами (денервация, голодание и т.п.). Задачей обзора было суммировать и проанализировать накопленный к настоящему времени массив данных о работе протеолитических систем при атро- фии скелетных мышц, вызванной гипокинезией или гипогравитацией. Особое внимание обращено на последние данные, свидетельствующие о значительной сигнальной роли протеолитических си- стем в процессах регуляции экспрессии генов и перестройки мышечного фенотипа.

TO THE EDITOR: This is a timely Point:Counterpoint that addresses the role of IGF-I in the regulation of muscle mass. Clearly, IGF-I is critical for muscle development and postnatal muscle growth (2). However, its role in the area of loadinduced muscle hypertrophy has been recently questioned (5). There are a few clarifications that should be made, in that the mice used in my study are not knockouts of the IGF-I receptor as implicated by Flüeck and Goldspink (6), but they are transgenic mice that contain a point mutation in the ATP binding domain resulting in abrogated IGF-I receptor function in a dominant negative fashion. Second, one of the key points of my findings was that it was possible for mechanical load to activate mTOR signaling independent of the IGF-I receptor. There are other critical pieces of evidence that must be considered as well. In response to acute loading, the increase in IGF-I production by the muscle occurs over a matter of days (1), while activation of the mTOR signaling is activated in a matter of minutes to hours (4). Furthermore, a major critical aspect of IGF-I signaling is Akt activation; however, the magnitude of phosphorylation and duration of activation of Akt in response to acute mechanical loading is substantially smaller compared to downstream components of mTOR (i.e. p70s6k) (4). Thus, unless IGF-I bypasses Akt to induce protein synthesis, it would suggest that mTOR is likely activated independent of Akt and IGF-I. Stewart and Pell (6) suggest that all muscle growth is dependent on satellite cell activation (6); however, mechanical load can induce smaller increases in muscle mass independent of satellite cell activation (3). Thus, if the major role of IGF-I is to affect satellite cell function and there are cases where we can get growth of muscle without satellite cell activation, then we must conclude IGF-I is not always necessary for muscle growth.

It has been shown that, after prolonged disuse, the accumulation of muscle mass and the recovery of soleus fibers volume are caused by water accumulation rather than protein synthesis intensification. At the same time, expression rate of the main markers of the activity of ubiquitin-proteasome system remained increased on the 3rd day of reloading and decreased to the control by the 7th day. Both the quantity of the insulin-like growth factor 1 and the number of satellite cells fused with muscle fibers and of myonuclei began to increase only on the 7th day of reloading. The data obtained evidenced a significant inertness of the postural muscle during its adaptation to the load (normal gravity) after prolonged disuse.

It has been shown that, after prolonged disuse, the accumulation of muscle mass and the recovery of soleus fiber volume are caused by water accumulation rather than protein synthesis intensification. At the same time, the expression rate of the main markers of the activity of ubiquitin-proteasome system remained increased on the 3rd day of reloading and decreased to the control by the 7th day. Both the quantity of the insulin-like growth factor 1 and the number of satellite cells fused with muscle fibers and of myonuclei began to increase only on the 7th day of reloading. The data obtained evidenced a significant inertness of the postural muscle during its adaptation to the load (normal gravity) after prolonged disuse.

The contractile properties of the postural soleus muscle were studied in rats at the early stage of gravitational unloading (three-day hindlimb suspension) with regard to different modes of muscle contraction (twitch and tetanic contraction of the isolated muscle and calcium-induced contraction of isolated skinned fibers). A significant (p < 0.01) enhancement of the peak twitch tension of the muscles of suspended rats without changes in time-dependent characteristics was observed, although the half-relaxation time tended to decrease. The fiber diameter did not change (42.37 ± 0.76 vs. 43.43 ± 1.15 μm in controls). The calcium-induced peak isometric tensions in control and unloaded soleus muscles were 37.6 ± 1.52 and 32.1 ± 1.05 mg, respectively (decrease significant at p < 0.05). No changes in threshold calcium concentration were recorded, but the pCa50 value in unloaded muscles decreased from 6.05 ± 0.02 in controls to 5.97 ± 0.02 (p ≤ 0.05), indicating loss of myofibrillar calcium sensitivity. The cooperativity coefficient ηn in control animals was 3.46 ± 0.16, and in suspended ones it decreased to 3.08 ± 0.11 (p < 0.05). Analysis with the Fluo-4AM calcium probe demonstrated that the intracellular Ca2+ concentration increased significantly after hindlimb suspension, whereas the relative contents of titin or nebulin did not change.

The modern conceptions of the structural organization and functional mechanisms of mitoKATP are discussed in the present review. Methods of the identification of the channel in the inner mitochondrial membrane and in intact cells are considered. The structure and properties of the channel, the mechanisms of its regulation with pharmacological modulators, redox agents (SH agents, NO and ROS), hormones etc. are reviewed. The authors adduce their own data concerning the structural organization, regulation, properties and the functional role of mitoKATP in the cell.

The activity of mitochondrial ATP-dependent potassium channel (mitoKATP) of rat heart and liver mitochondria was shown to decrease during aging. This partially explains the increase of risk of ischemia at a mature age since mitoKATP activation provides cardioprotection. We demonstrated that uridine-5'-diphosphate (UDP) possesses the property to activate mitoKATP. At a concentration of 30 microM, it reactivated mitoKATP in mitochondria, and 5-hydroxydecanoate (5-HD) eliminated this effect. In experimental animals, UDP precursors uridine and uridine-5'-monophosphate (UMP) (both 30 mg/kg, administered intravenously 5 min before coronary occlusion) decreased the myocardium ischemic alteration index (1.9 and 3.5 times, respectively) and the T-wave amplitude within 60 min after occlusion. Both effects were inhibited by Glibenclamide (Glib) and 5-HD. UMP and uridine decreased the number of premature ventricular beats 5.6 and 1.9 times and the duration of ventricular tachycardia 9.4 and 4.1 times, respectively. Glib and 5-HD inhibited the anti-arrhythmic parameters, 5-HD being less effective. Uridine and UMP decreased the duration of fibrillation 10.8 and 3.6 times, respectively, and this effect was not abolished by Glib and 5-HD. Thus, uridine and UMP, which are the precursors of UDP in the cell, possess cardioprotective properties. MitoKATP prevents mainly ischemic injuries and partially rhythm disorders.