In this study, muscle-specific BDNF knockout animals were generated and compared with BDNF−/− knockouts. Our findings show that muscle-derived BDNF plays an important role in 1) regulating satellite cell proliferation and differentiation and 2) early regeneration after muscle injury.
J. Neurochem. (2012) 120, 230–238. Abstract Brain‐derived neurotrophic factor (BDNF) is required for efficient skeletal‐muscle regeneration and perturbing its expression causes abnormalities in the proliferation and differentiation of skeletal muscle cells. In this study, we investigated the mechanism of BDNF suppression that occurs during myogenic differentiation. BDNF is expressed at the mRNA level as two isoforms that differ in the length of their 3′UTRs as a result of alternative cleavage and polyadenylation. Sequence analysis revealed the presence of three miR‐206 target sites in the long BDNF 3′UTR (BDNF‐L), whereas only one site was found in the short mRNA BDNF 3′UTR (BDNF‐S). miR‐206 is known to regulate the differentiation of C2C12 myoblasts and its expression is induced during the transition from myoblasts to myotubes. We thus examined whether miR‐206‐mediated suppression is responsible for the expression pattern of BDNF during myogenic differentiation. BDNF‐L was suppressed to a greater extent than BDNF‐S during differentiation of C2C12 myoblasts. Transfection of a miR‐206 precursor decreased activity of reporters representative of the BDNF‐L 3′UTR, but not BDNF‐S 3′UTR, and repressed endogenous BDNF mRNA levels. This suppression was found to be dependent on the presence of multiple miR‐206 target sites in the BDNF‐L 3′UTR. Conversely, suppression of miR‐206 levels resulted in de‐repression of BDNF 3′UTR reporter activity and increased endogenous BDNF‐L mRNA levels. A receptor for BDNF, p75NTR, was also suppressed during differentiation and in response to miR‐206, but this appeared to not be entirely mediated via a miR‐206 target site its 3′UTR. Based on these observations, BDNF represents a novel target through which miR‐206 controls the initiation and maintenance of the differentiated state of muscle cells. These results further suggest that miR‐206 might play a role in regulating retrograde signaling of BDNF at the neuromuscular junction.
Banas K, Clow C, Jasmin BJ, Renaud JM. The KATP channel Kir6.2 subunit content is higher in glycolytic than oxidative skeletal muscle fibers. Am J Physiol Regul Integr Comp Physiol 301: R916 -R925, 2011. First published June 29, 2011 doi:10.1152/ajpregu.00663.2010.-It has long been suggested that in skeletal muscle, the ATP-sensitive K ϩ channel (KATP) channel is important in protecting energy levels and that abolishing its activity causes fiber damage and severely impairs function. The responses to a lack of K ATP channel activity vary between muscles and fibers, with the severity of the impairment being the highest in the most glycolytic muscle fibers. Furthermore, glycolytic muscle fibers are also expected to face metabolic stress more often than oxidative ones. The objective of this study was to determine whether the t-tubular K ATP channel content differs between muscles and fiber types. K ATP channel content was estimated using a semiquantitative immunofluorescence approach by staining cross sections from soleus, extensor digitorum longus (EDL), and flexor digitorum brevis (FDB) muscles with anti-Kir6.2 antibody. Fiber types were determined using serial cross sections stained with specific antimyosin I, IIA, IIB, and IIX antibodies. Changes in Kir6.2 content were compared with changes in CaV1.1 content, as this Ca 2ϩ channel is responsible for triggering Ca 2ϩ release from sarcoplasmic reticulum. The Kir6.2 content was the lowest in the oxidative soleus and the highest in the glycolytic EDL and FDB. At the individual fiber level, the Kir6.2 content within a muscle was in the order of type IIB Ͼ IIX Ͼ IIA Ն I. Interestingly, the Kir6.2 content for a given fiber type was significantly different between soleus, EDL, and FDB, and highest in FDB. Correlations of relative fluorescence intensities from the Kir6.2 and CaV1.1 antibodies were significant for all three muscles. However, the variability in content between the three muscles or individual fibers was much greater for Kir6.2 than for CaV1.1. It is suggested that the t-tubular K ATP channel content increases as the glycolytic capacity increases and as the oxidative capacity decreases and that the expression of K ATP channels may be linked to how often muscles/ fibers face metabolic stress. muscle fatigue; KATP channels; fiber type THE ACTIVITY OF THE ATP-SENSITIVE K ϩ channel (K ATP channel) is primarily regulated by the energy state of the cell. It is activated by decreases in intracellular ATP and intracellular pH and increases in intracellular ADP levels (10,14). It is also activated by increases in extracellular adenosine concentration (4), which is produced during metabolic stress. There is now good evidence for the activation of K ATP channels during metabolic stress, such as fatigue and ischemia (3, 29). Thus, the K ATP channel behaves as an energy sensor that is activated when energy levels become low, and, as such, links the cell energy state to the electrical activity of the cell membrane. The channel is also vital in preventing fiber damage dur...
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