Cell states in hematopoiesis are controlled by master regulators and by complex circuits of a growing family of RNA species impacting cell phenotype maintenance and plasticity. Circular RNAs (circRNAs) are rapidly gaining the status of particularly stable transcriptome members with distinctive qualities. RNA-seq identified thousands of circRNAs with developmental stage- and tissue-specific expression corroborating earlier suggestions that circular isoforms are a natural feature of the cell expression program. CircRNAs are abundantly expressed also in the hematopoietic compartment. There are a number of studies on circRNAs in blood cells, a specific overview is however lacking. In this review we first present current insight in circRNA biogenesis discussing the relevance for hematopoiesis of the highly interleaved processes of splicing and circRNA biogenesis. Regarding molecular functions circRNAs modulate host gene expression, but also compete for binding of microRNAs, RNA-binding proteins or translation initiation and participate in regulatory circuits. We examine circRNA expression in the hematopoietic compartment and in hematologic malignancies and review the recent breakthrough study that identified pathogenic circRNAs derived from leukemia fusion genes. CircRNA high and regulated expression in blood cell types indicate that further studies are warranted to inform the position of these regulators in normal and malignant hematopoiesis.
1. Force measurements in isolated myofibrils (15 'C; sarcomere length, 2 10 ,um) were used in this study to determine whether sarcomeric proteins are responsible for the large differences in the amounts of active and passive tension of cardiac versus skeletal muscle. Single myofibrils and bundles of two to four myofibrils were prepared from glycerinated tibialis anterior and sartorius muscles of the frog. Skinned frog atrial myocytes were used as a model for cardiac myofibrils. 2. Electron microscope analysis of the preparations showed that: (i) frog atrial myocytes contained a small and variable number of individual myofibrils (from 1 to 7); (ii) the mean cross-sectional area and mean number of myosin filaments of individual cardiac myofibrils did not differ significantly from those of single skeletal myofibrils; and (iii) the total myofibril cross-sectional area of atrial myocytes was on average comparable to that of bundles of two to four skeletal myofibrils. 3. In maximally activated skeletal preparations, values of active force ranged from 0 45 + 0 03 1sN for the single myofibrils (mean + S.E.M.; n = 16) to 1X44 + 024 1uN for the bundles of two to four myofibrils (n = 9). Maximum active force values of forty-five cardiac myocytes averaged 1P47 + 0 10 ,uN and exhibited a non-continuous distribution with peaks at intervals of about 0 5 1sN. The results suggest that variation in active force among cardiac preparations mainly reflects variability in the number of myofibrils inside the myocytes and that individual cardiac myofibrils develop the same average amount of force as single skeletal myofibrils. 4. The mean sarcomere length-resting force relation of atrial myocytes could be superimposed on that of bundles of two to four skeletal myofibrils. This suggests that, for any given amount of strain, individual cardiac and skeletal sarcomeres bear essentially the same passive force. 5. The length-passive tension data of all preparations could be fitted by an exponential equation. Equation parameters obtained for both types of myofibrils were in reasonable agreement with those reported for larger preparations of frog skeletal muscle but were very different from those estimated for multicellular frog atrial preparations. It is concluded that myofibrils are the major determinant of resting tension in skeletal muscle; structures other than the myofibrils are responsible for the high passive stiffness of frog cardiac muscle.
SUMMARY1. The velocity of 'unloaded' shortening (VO) and the force-velocity relation were studied during fused tetani (0-5-2-0 TC) in short successive segments along the entire length of single fibres isolated from the tibialis anterior muscle of Rana temporaria. The segments were defined by opaque markers of hair that were placed on the fibre surface, 0-5-0 8 mm apart, from one tendon insertion to the other. The change in distance between two adjacent markers (one segment) was monitored by means of a photoelectric recording system, while the fibre was released to shorten isotonically between 2X2 and 2-0 gsm sarcomere lengths. The accuracy of the V0 measurement was better than 4 % in all parts of the fibre.2. V0 varied along the length of the fibre, each fibre having a unique velocity pattern that remained constant throughout the experiment. The difference between the highest and lowest values of V0 within the fibre varied between 11 and 45 % of the fibre mean in thirty-two preparations (mean difference 23 + 2 %, S.E. of mean).3. An attempt was made to relate the V0 pattern to the fibre's orientation in the body in fourteen complete experiments. The highest values of VI were obtained near the proximal end ofthe fibre, and there was a clear trend for V0 to assume lower values towards the distal end.4. The V1 pattern along the fibre did not correlate with the segments' capacities to produce force nor with the passive viscoelastic properties of the segments.5. Force-velocity data obtained from individual segments provided a good fit to Hill's (1938) 6. The results support the view that the kinetic properties of the myofilament system differ from one region to another along the length of a muscle fibre.
SUMMARY1. The velocity of unloaded shortening (VI), the myofibrillar ATPase activity and the immunoreactivity to two monoclonal antibodies (A1 and A2) that were raised against the myosin heavy chains were studied in single fibres of the anterior tibialis muscle of Rana temporaria. VO was recorded for the fibre as a whole using the slacktest method. Myofibrillar ATPase activity was determined by means of a quantitative histochemical technique.2. A highly significant, direct relationship was found to exist between V0 and the myofibrillar ATPase activity recorded in the same single fibres. Both VJ and the myofibrillar ATPase activity changed in proportion to the cross-sectional area of the fibres.3. Muscle fibres that had first been characterized with respect to V0 and myofibrillar ATPase activity were exposed to monoclonal antibodies Al and A2. Thin fibres, having relatively low V0 and low myofibrillar ATPase activity, reacted preferentially with A 1. Thick fibres, on the other hand, exhibiting relatively high V0 and high myofibrillar ATPase activity, were preferentially stained by A2. A third category of fibres reacted with both Al and A2. The results support the view that the variability in shortening velocity and myofibrillar ATPase activity that exists among twitch fibres in frog skeletal muscle is based on differences in myosin heavychain composition.4. Attempts were made to elucidate further the previous observation (Edman, Reggiani & te that the velocity of unloaded shortening (V0) differs along the length of individual muscle fibres. To this end discrete segments (0 5-0 7 mm in length) of intact fibres were delineated by opaque markers of hair that were placed on the fibre surface. The change in length between two adjacent markers (one segment) was recorded photo-electrically while the fibre was released to shorten against a very small load between 2-2 and 2-0 sm sarcomere lengths. In the majority of fibres (eight out of eleven preparations), V0 and myofibrillar ATPase activity exhibited similar patterns of variation along the fibre. Pooled data from thirty-three segments of twelve fibres showed a positive correlation between V0 and myofibrillar ATPase activity (P < 005).* On study leave from the Institute of Human Physiology, University of Pavia, Italy. K. A. P. EDMAN AND OTHERS5. The possibility was explored that the myosin isoform composition might vary along the length of an individual muscle fibre. For this purpose bundles of fibres were cross-sectioned at 0 5-1 mm intervals along their entire length and the reactivity to monoclonal antibody A2 was tested at each location. Clear differences in immunoreactivity tc A2 were demonstrable along the length of ten out of sixty-six fibres examined. These results provide evidence that the myosin heavy-chain composition may differ from one region to another within a single muscle fibre. Such a variation in myosin isoform composition may, at least partly, account for the segmental differences in contractile properties that are found to exist along the length of...
The effects of growth and limb immobilization on muscle mass, total physiological cross-section (PC), the number of sarcomeres in series and the length of sarcomere components were investigated in the soleus muscle (SOL) and compared to previously obtained data on gastrocnemius (GM) muscles of rats between age 10 and 16 weeks. For SOL this period of growth was reflected in an increased muscle mass and PC. No such increases were found for GM. In contrast, immobilization caused severe atrophy of fibres of both muscles. Compared to the value at the start of the immobilization, it was found that the fast twitch muscle (GM) atrophied more than the typically slow twitch one (SOL). The number of sarcomeres in series within fibres increased after growth and decreased after immobilization of SOL. For fibres of GM no such changes were observed. Muscle architecture is proposed as an important factor for the explanation of the results concerning the number of sarcomeres in series and those arranged in parallel. Due to the difference in muscle architecture, GM being more pennate than SOL, during growth, it is thought that increases in bone length affect the length of fibres of SOL more than those of GM. During immobilization, atrophy of fibres of GM was sufficient for the muscle length adaptation to meet the muscle length change induced by immobilization but in SOL, atrophy had to be accompanied by decreases in the number of sarcomeres in series to achieve adequate muscle length adaptation.
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