Age-associated muscle atrophy is a debilitating condition associated with loss of muscle mass and function with age that contributes to limitation of mobility and locomotion. However, the underlying ...mechanisms of how intrinsic muscle changes with age are largely unknown. Here we report that, with age, Mind bomb-1 (Mib1) plays important role in skeletal muscle maintenance via proteasomal degradation-dependent regulation of α-actinin 3 (Actn3). The disruption of Mib1 in myofibers (Mib1
) results in alteration of type 2 glycolytic myofibers, muscle atrophy, impaired muscle function, and Actn3 accumulation. After chronic exercise, Mib1
mice show muscle atrophy even at young age. However, when Actn3 level is downregulated, chronic exercise-induced muscle atrophy is ameliorated. Importantly, the Mib1 and Actn3 levels show clinical relevance in human skeletal muscles accompanied by decrease in skeletal muscle function with age. Together, these findings reveal the significance of the Mib1-Actn3 axis in skeletal muscle maintenance with age and suggest the therapeutic potential for the treatment or amelioration of age-related muscle atrophy.
The survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the ...central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atrophy, recent studies have also revealed the requirement of SMN in non-neuronal cells in the peripheral regions. Here, we report that the fibro-adipogenic progenitor subpopulation expressing Dpp4 (Dpp4+ FAPs) is required for the neuromuscular system. Furthermore, we also reveal that BRCA1-associated protein-1 (Bap1) is crucial for the stabilization of SMN in FAPs by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to loss of motor neurons and muscle atrophy. Overexpression of the ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degeneration. In addition, transplantation of Dpp4+ FAPs, but not Dpp4- FAPs, completely rescued neuromuscular defects. Our data reveal the crucial role of Bap1-mediated SMN stabilization in Dpp4+ FAPs for the neuromuscular system and provide the possibility of cell-based therapeutics to treat neuromuscular diseases.
Background
With organismal aging, the hypothalamic–pituitary–gonadal (HPG) activity gradually decreases, resulting in the systemic functional declines of the target tissues including skeletal ...muscles. Although the HPG axis plays an important role in health span, how the HPG axis systemically prevents functional aging is largely unknown.
Methods
We generated muscle stem cell (MuSC)‐specific androgen receptor (Ar) and oestrogen receptor 2 (Esr2) double knockout (dKO) mice and pharmacologically inhibited (Antide) the HPG axis to mimic decreased serum levels of sex steroid hormones in aged mice. After short‐term and long‐term sex hormone signalling ablation, the MuSCs were functionally analysed, and their aging phenotypes were compared with those of geriatric mice (30‐month‐old). To investigate pathways associated with sex hormone signalling disruption, RNA sequencing and bioinformatic analyses were performed.
Results
Disrupting the HPG axis results in impaired muscle regeneration wild‐type (WT) vs. dKO, P < 0.0001; Veh vs. Antide, P = 0.004. The expression of DNA damage marker (in WT = 7.0 ± 1.6%, dKO = 32.5 ± 2.6%, P < 0.01; in Veh = 13.4 ± 4.5%, Antide = 29.7 ± 5.5%, P = 0.028) and senescence‐associated β‐galactosidase activity (in WT = 3.8 ± 1.2%, dKO = 10.3 ± 1.6%, P < 0.01; in Veh = 2.1 ± 0.4%, Antide = 9.6 ± 0.8%, P = 0.005), as well as the expression levels of senescence‐associated genes, p16Ink4a and p21Cip1, was significantly increased in the MuSCs, indicating that genetic and pharmacological inhibition of the HPG axis recapitulates the progressive aging process of MuSCs. Mechanistically, the ablation of sex hormone signalling reduced the expression of transcription factor EB (Tfeb) and Tfeb target gene in MuSCs, suggesting that sex hormones directly induce the expression of Tfeb, a master regulator of the autophagy–lysosome pathway, and consequently autophagosome clearance. Transduction of the Tfeb in naturally aged MuSCs increased muscle mass control geriatric MuSC transplanted tibialis anterior (TA) muscle = 34.3 ± 2.9 mg, Tfeb‐transducing geriatric MuSC transplanted TA muscle = 44.7 ± 6.7 mg, P = 0.015 and regenerating myofibre size eMyHC+tdTomato+ myofibre cross‐section area (CSA) in control vs. Tfeb, P = 0.002 after muscle injury.
Conclusions
Our data show that the HPG axis systemically controls autophagosome clearance in MuSCs through Tfeb and prevents MuSCs from senescence, suggesting that sustained HPG activity throughout life regulates autophagosome clearance to maintain the quiescence of MuSCs by preventing senescence until advanced age.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Myogenic progenitors (MPs) generate myocytes that fuse to form myofibers during skeletal muscle development while maintaining the progenitor pool, which is crucial for generating sufficient muscle. ...Notch signaling has been known to reserve a population of embryonic MPs during primary myogenesis by promoting cell cycle exit and suppressing premature differentiation. However, the roles of individual Notch receptors (Notch1-4) during embryonic/fetal myogenesis are still elusive. In this study, we found that Notch1 and Notch2, which exhibit the highest structural similarity among Notch receptors, maintain the MP population by distinct mechanisms: Notch1 induces cell cycle exit and Notch2 suppresses premature differentiation. Moreover, genetic and cell culture studies showed that Notch1 and Notch2 signaling in MPs are distinctively activated by interacting with Notch ligand-expressing myofibers and MP-lineage cells, respectively. These results suggest that through different activation modes, Notch1 and Notch2 distinctively and cooperatively maintain MP population during fetal myogenesis for proper muscle development.
During exercise, skeletal muscle is exposed to a low oxygen condition, hypoxia. Under hypoxia, the transcription factor hypoxia-inducible factor-1α (HIF-1α) is stabilized and induces expressions of ...its target genes regulating glycolytic metabolism. Here, using a skeletal muscle-specific gene ablation mouse model, we show that Brg1/Brm-associated factor 155 (Baf155), a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is essential for HIF-1α signaling in skeletal muscle. Muscle-specific ablation of Baf155 increases oxidative metabolism by reducing HIF-1α function, which accompanies the decreased lactate production during exercise. Furthermore, the augmented oxidation leads to high intramuscular adenosine triphosphate (ATP) level and results in the enhancement of endurance exercise capacity. Mechanistically, our chromatin immunoprecipitation (ChIP) analysis reveals that Baf155 modulates DNA-binding activity of HIF-1α to the promoters of its target genes. In addition, for this regulatory function, Baf155 requires a phospho-signal transducer and activator of transcription 3 (pSTAT3), which forms a coactivator complex with HIF-1α, to activate HIF-1α signaling. Our findings reveal the crucial role of Baf155 in energy metabolism of skeletal muscle and the interaction between Baf155 and hypoxia signaling.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient ...therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre-symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination-resistant variant of survival motor neuron (SMN), SMN
, has improved therapeutic effects for SMA compared with wild-type SMN (SMN
).
A severe SMA mouse model, SMA type 1.5 (Smn
; SMN2
; SMN∆7
) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMN
and AAV9-SMN
. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle.
AAV9-SMN
-treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMN
-treated mice. Lifespan increased by more than 10-fold in AAV9-SMN
-treated mice (144.8 ± 26.11 days) as compared with AAV9-SMN
-treated mice (26.8 ± 1.41 days). AAV9-SMN
-treated mice showed an ascending weight pattern, unlike AAV9-SMN
-treated mice, which only gained weight until P20 up to 5 g on average. Several motor function tests showed the improved therapeutic efficacy of SMN
. In the negative geotaxis test, AAV9-SMN
-treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMN
-treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMN
-treated mice, unlike AAV9-SMN
-treated mice that showed clasping phenotype for more than 20 out of 30 s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMN
-treated mice compared with AAV9-SMN
-treated mice without prominent neurotoxicity. AAV9-SMN
had fewer liver defects compared with AAV9-SMN
, as judged by increased proliferation of hepatocytes (P < 0.0001) and insulin-like growth factor-1 production (P < 0.0001). Especially, low-dose AAV9-SMN
(nine-fold) also reduced clasping time compared with SMN
.
SMN
will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low-dose treatment of SMA patients with AAV9-SMN
can reduce the adverse events of Zolgensma. Collectively, SMN
has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Intersubband (intraband) transitions allow absorption of photons in the infrared spectral regime, which is essential for IR-photodetector and optical communication applications. Among various ...technologies, nanodisks embedded in nanowires offer a unique opportunity to be utilized in intraband devices due to the ease of tuning the fundamental parameters such as strain distribution, band energy, and confinement of the active region. Here, we show the transverse electric polarized intraband absorption using InGaN/GaN nanodisks cladded by AlGaN. Fourier transform infrared reflection (FTIR) measurement confirms absorption of normal incident in-plane transverse electric polarized photons in the mid-IR regime (wavelength of ~ 15 μm) at room temperature. The momentum matrix of the nanodisk energy states indicates electron transition from the ground state s into the p
or p
orbital-like excited states. Furthermore, the absorption characteristics depending on the indium composition and nanowire diameter exhibits tunability of the intraband absorption spectra within the nanodisks. We believe nanodisks embedded nanowires is a promising technology for achieving tunable detection of photons in the IR spectrum.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Deep-ultraviolet (DUV) photodetectors based on wide-band-gap semiconductors have attracted significant interest across a wide range of applications in the industrial, biological, environmental, and ...military fields due to their solar-blind nature. As one of the most promising wide-band-gap materials, β-Ga2O3 provides great application potential over detection wavelengths ranging from 230 to 280 nm owing to its superior optoelectronic performance, stability, and compatibility with conventional fabrication techniques. Although various innovative approaches and device configurations have been applied to achieve highly performing β-Ga2O3 DUV photodetectors, the highest demonstrated responsivity of the β-Ga2O3 photodetectors has only been around 105 A/W. Here, we demonstrate a β-Ga2O3 phototransistor with an ultrahigh responsivity of 2.4 × 107 A/W and a specific detectivity of 1.7 × 1015 Jones, achieved by engineering a photogating effect. A β-Ga2O3/MgO heterostructure with an Al2O3 encapsulation layer is employed not only to reduce photogenerated electron/hole recombination but also to suppress the photoconducting effects at the back-channel surface of the β-Ga2O3 phototransistor via a defect-assisted charge transfer mechanism. The measured photoresponsivity is almost 2 orders of magnitude higher than the highest previously reported value in a β-Ga2O3-based photodetector, to the best of our knowledge. We believe that the demonstrated β-Ga2O3/MgO heterostructure configuration, combined with its facile fabrication method, will pave the way for the development of ultrasensitive DUV photodetectors utilizing oxide-based wide-band-gap materials.
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IJS, KILJ, NUK, PNG, UL, UM
In this study, we demonstrate ferroelectric GaN high-electron mobility transistors (HEMTs) with a sputtered AlScN gate dielectric, exhibiting a large memory window of ~ 14.6 V and a high on/off ratio ...of ~ 10 8 . The strong polarization of AlScN layer contributes to the remarkably large threshold voltage (V th ) tuning range with counterclockwise hysteresis depending on voltage sweep ranges and pulsed parameters. Moreover, a recessed-gate structure enables the pulsed enhancement and depletion mode switching. The reconfigurable V th via pulse modulation further allows feasibility of NOR logic gate with the single ferroelectric GaN HEMT.
Significant effort for demonstrating a gallium nitride (GaN)-based ferroelectric metal–oxide–semiconductor (MOS)-high-electron-mobility transistor (HEMT) for reconfigurable operation via simple pulse ...operation has been hindered by the lack of suitable materials, gate structures, and intrinsic depolarization effects. In this study, we have demonstrated artificial synapses using a GaN-based MOS-HEMT integrated with an α-In2Se3 ferroelectric semiconductor. The van der Waals heterostructure of GaN/α-In2Se3 provides a potential to achieve high-frequency operation driven by a ferroelectrically coupled two-dimensional electron gas (2DEG). Moreover, the semiconducting α-In2Se3 features a steep subthreshold slope with a high ON/OFF ratio (∼1010). The self-aligned α-In2Se3 layer with the gate electrode suppresses the in-plane polarization while promoting the out-of-plane (OOP) polarization of α-In2Se3, resulting in a steep subthreshold slope (10 mV/dec) and creating a large hysteresis (2 V). Furthermore, based on the short-term plasticity (STP) characteristics of the fabricated ferroelectric HEMT, we demonstrated reservoir computing (RC) for image classification. We believe that the ferroelectric GaN/α-In2Se3 HEMT can provide a viable pathway toward ultrafast neuromorphic computing.
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IJS, KILJ, NUK, PNG, UL, UM
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