scholarly journals Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

2008 ◽  
Vol 19 (2) ◽  
pp. 553-562 ◽  
Author(s):  
Anthony Cammarato ◽  
Corey M. Dambacher ◽  
Aileen F. Knowles ◽  
William A. Kronert ◽  
Rolf Bodmer ◽  
...  
Keyword(s):  
Motor Function ◽  
Striated Muscle ◽  
Molecular Motor ◽  
Restrictive Cardiomyopathy ◽  
Integrative Approach ◽  
Muscle Disorders ◽  
Dilatory Response ◽  
Cardiac Muscles ◽  
And Performance

Striated muscle myosin is a multidomain ATP-dependent molecular motor. Alterations to various domains affect the chemomechanical properties of the motor, and they are associated with skeletal and cardiac myopathies. The myosin transducer domain is located near the nucleotide-binding site. Here, we helped define the role of the transducer by using an integrative approach to study how Drosophila melanogaster transducer mutations D45 and Mhc5affect myosin function and skeletal and cardiac muscle structure and performance. We found D45 (A261T) myosin has depressed ATPase activity and in vitro actin motility, whereas Mhc5(G200D) myosin has these properties enhanced. Depressed D45 myosin activity protects against age-associated dysfunction in metabolically demanding skeletal muscles. In contrast, enhanced Mhc5myosin function allows normal skeletal myofibril assembly, but it induces degradation of the myofibrillar apparatus, probably as a result of contractile disinhibition. Analysis of beating hearts demonstrates depressed motor function evokes a dilatory response, similar to that seen with vertebrate dilated cardiomyopathy myosin mutations, and it disrupts contractile rhythmicity. Enhanced myosin performance generates a phenotype apparently analogous to that of human restrictive cardiomyopathy, possibly indicating myosin-based origins for the disease. The D45 and Mhc5mutations illustrate the transducer's role in influencing the chemomechanical properties of myosin and produce unique pathologies in distinct muscles. Our data suggest Drosophila is a valuable system for identifying and modeling mutations analogous to those associated with specific human muscle disorders.

Effects of endurance training on apoptotic susceptibility in striated muscle

2011 ◽  
Vol 110 (6) ◽  
pp. 1638-1645 ◽  
Author(s):  
Anna Vainshtein ◽  
Lawrence Kazak ◽  
David A. Hood
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Striated Muscle ◽  
Striated Muscles ◽  
Apoptotic Signaling ◽  
Muscle Disuse ◽  
Mitochondrial Fractions ◽  
Cardiac Muscles ◽  
Apoptosis Inducing Factor

An increase in the production of reactive oxygen species occurs with muscle disuse, ischemic cardiomyopathy, and conditions that arise with senescence. The resulting oxidative stress is associated with apoptosis-related myopathies. Recent research has suggested that chronic exercise is protective against mitochondrially mediated programmed cell death. To further investigate this, we compared soleus (Sol) and cardiac muscles of voluntary wheel-trained (T; 10 wk) and untrained (C) animals. Training produced a 52% increase in muscle cytochrome c oxidase (COX) activity. Sol and left ventricle (LV) strips were isolated and incubated in vitro with H2O2 for 4 h. Strips were then fractionated into cytosolic and mitochondrial fractions. Whole muscle apoptosis-inducing factor (AIF) and Bax/Bcl-2 levels were reduced in both the Sol and LV from T animals. H2O2 treatment induced increases in JNK phosphorylation, cofilin-2 localization to the mitochondria, as well as cytosolic AIF in both Sol and LV of T and C animals, respectively. Mitochondrial Bax and cytosolic cytochrome c were augmented under oxidative stress in the LV only. The H2O2-induced increases in P-JNK, mitochondrial Bax, and cytosolic AIF were ablated in the LV of T animals. These data suggest that short-term oxidative stress can induce apoptotic signaling in striated muscles in vitro. In addition, training can attenuate oxidative stress-induced apoptotic signaling in a tissue-specific manner, with an effect that is most prominent in cardiac muscle.

scholarly journals A myosin II-based nanomachine devised for the study of Ca2+-dependent mechanisms of muscle regulation

2020 ◽  
Author(s):  
Irene Pertici ◽  
Giulio Bianchi ◽  
Lorenzo Bongini ◽  
Vincenzo Lombardi ◽  
Pasquale Bianco
Keyword(s):  
Optical Tweezers ◽  
Actin Filament ◽  
Striated Muscle ◽  
Molecular Motor ◽  
Myosin Ii ◽  
Psoas Muscle ◽  
Cytoskeletal Proteins ◽  
Actin Binding ◽  
Emergent Properties

AbstractThe emergent properties of the array arrangement of the molecular motor myosin II in the sarcomere of the striated muscle, generation of steady force and shortening, can be studied in vitro with a synthetic nanomachine, made by an ensemble of eight HMM myosin fragments from rabbit psoas muscle carried on a piezoelectric nanopositioner and brought to interact with a properly oriented actin filament attached via gelsolin (a Ca2+-regulated actin binding protein) to a bead trapped by a Dual Laser Optical Tweezers. The application of the original version of the nanomachine to investigation of the Ca2+-dependent regulation mechanisms of the other sarcomeric (regulatory or cytoskeleton) proteins, adding them on at a time, was anyway prevented by the impossibility to preserve Ca2+ as a free parameter. Here the nanomachine is implemented by assembling the bead-attached actin filament with the Ca2+-insensitive gelsolin fragment TL40. The performance of the nanomachine is determined either in the absence or in the presence of 0.1 mM Ca2+ (the concentration required for BTA preparation with gelsolin). The nanomachine exhibits a maximum power output of 5.4 aW, independently of [Ca2+], opening the possibility for future studies of the Ca2+-dependent function/dysfunction of regulatory and cytoskeletal proteins.

scholarly journals A Myosin II-Based Nanomachine Devised for the Study of Ca2+-Dependent Mechanisms of Muscle Regulation

2020 ◽  
Vol 21 (19) ◽  
pp. 7372
Author(s):  
Irene Pertici ◽  
Giulio Bianchi ◽  
Lorenzo Bongini ◽  
Vincenzo Lombardi ◽  
Pasquale Bianco
Keyword(s):  
Optical Tweezers ◽  
Actin Filament ◽  
Striated Muscle ◽  
Molecular Motor ◽  
Myosin Ii ◽  
Psoas Muscle ◽  
Cytoskeletal Proteins ◽  
Actin Binding ◽  
Emergent Properties

The emergent properties of the array arrangement of the molecular motor myosin II in the sarcomere of the striated muscle, the generation of steady force and shortening, can be studied in vitro with a synthetic nanomachine made of an ensemble of eight heavy-meromyosin (HMM) fragments of myosin from rabbit psoas muscle, carried on a piezoelectric nanopositioner and brought to interact with a properly oriented actin filament attached via gelsolin (a Ca2+-regulated actin binding protein) to a bead trapped by dual laser optical tweezers. However, the application of the original version of the nanomachine to investigate the Ca2+-dependent regulation mechanisms of the other sarcomeric (regulatory or cytoskeleton) proteins, adding them one at a time, was prevented by the impossibility to preserve [Ca2+] as a free parameter. Here, the nanomachine is implemented by assembling the bead-attached actin filament with the Ca2+-insensitive gelsolin fragment TL40. The performance of the nanomachine is determined both in the absence and in the presence of Ca2+ (0.1 mM, the concentration required for actin attachment to the bead with gelsolin). The nanomachine exhibits a maximum power output of 5.4 aW, independently of [Ca2+], opening the possibility for future studies of the Ca2+-dependent function/dysfunction of regulatory and cytoskeletal proteins.

The Safety and Antimicrobial Properties of Stabilized Hypochlorous Acid in Acetic Acid Buffer for the Treatment of Acute Wounds—a Human Pilot Study and In Vitro Data

2021 ◽  
pp. 153473462110156
Author(s):  
Ewa A. Burian ◽  
Lubna Sabah ◽  
Klaus Kirketerp-Møller ◽  
Elin Ibstedt ◽  
Magnus M. Fazli ◽  
...  
Keyword(s):  
Pilot Study ◽  
Hypochlorous Acid ◽  
Treatment Time ◽  
Donor Site ◽  
Antimicrobial Properties ◽  
Prolonged Treatment ◽  
Wound Irrigation ◽  
The Mean ◽  
And Performance

Acute wounds may require cleansing to reduce the risk of infection. Stabilized hypochlorous acid in acetic buffer (HOCl + buffer) is a novel wound irrigation solution with antimicrobial properties. We performed a first-in-man, prospective, open-label pilot study to document preliminary safety and performance in the treatment of acute wounds. The study enrolled 12 subjects scheduled for a split-skin graft transplantation, where the donor site was used as a model of an acute wound. The treatment time was 75 s, given on 6 occasions. A total of 7 adverse events were regarded as related to the treatment; all registered as pain during the procedure for 2 subjects. One subject had a wound infection at the donor site. The mean colony-forming unit (CFU) decreased by 41% after the treatment, and the mean epithelialization was 96% on both days 14 (standard deviation [SD] 8%) and 21 (SD 10%). The study provides preliminary support for the safety, well-tolerance, and efficacy of HOCl + buffer for acute wounds. The pain was frequent although resolved quickly. Excellent wound healing and satisfying antimicrobial properties were observed. A subsequent in vitro biofilm study also indicated good antimicrobial activity against Pseudomonas aeruginosa with a 96% mean reduction of CFU, when used for a treatment duration of 15 min ( P < .0001), and a 50% decrease for Staphylococcus aureus ( P = .1010). Future larger studies are needed to evaluate the safety and performance of HOCl + buffer in acute wounds, including the promising antimicrobial effect by prolonged treatment on bacterial biofilms.

scholarly journals Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

2021 ◽  
Vol 22 (8) ◽  
pp. 4256
Author(s):  
Lorenzo Maggi ◽  
Manolis Mavroidis ◽  
Stelios Psarras ◽  
Yassemi Capetanaki ◽  
Giovanna Lattanzi
Keyword(s):  
Muscular Dystrophy ◽  
Cardiac Muscle ◽  
Intermediate Filament ◽  
Striated Muscle ◽  
Congenital Muscular Dystrophy ◽  
Left Ventricular ◽  
Intermediate Filament Proteins ◽  
Muscle Disorders ◽  
Genes Encoding ◽  
Molecular Aspects

Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery–Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

scholarly journals The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 710
Author(s):  
Tanja Ilić ◽  
Ivana Pantelić ◽  
Snežana Savić
Keyword(s):  
Statistical Power ◽  
Failure Modes ◽  
In Vitro Release ◽  
Optimal Number ◽  
Drug Products ◽  
Pharmaceutical Equivalence ◽  
And Performance ◽  
Low Sensitivity

Due to complex interdependent relationships affecting their microstructure, topical semisolid drug formulations face unique obstacles to the development of generics compared to other drug products. Traditionally, establishing bioequivalence is based on comparative clinical trials, which are expensive and often associated with high degrees of variability and low sensitivity in detecting formulation differences. To address this issue, leading regulatory agencies have aimed to advance guidelines relevant to topical generics, ultimately accepting different non-clinical, in vitro/in vivo surrogate methods for topical bioequivalence assessment. Unfortunately, according to both industry and academia stakeholders, these efforts are far from flawless, and often upsurge the potential for result variability and a number of other failure modes. This paper offers a comprehensive review of the literature focused on amending regulatory positions concerning the demonstration of (i) extended pharmaceutical equivalence and (ii) equivalence with respect to the efficacy of topical semisolids. The proposed corrective measures are disclosed and critically discussed, as they span from mere demands to widen the acceptance range (e.g., from ±10% to ±20%/±25% for rheology and in vitro release parameters highly prone to batch-to-batch variability) or reassess the optimal number of samples required to reach the desired statistical power, but also rely on specific data modeling or novel statistical approaches.

scholarly journals The Topical Nanodelivery of Vismodegib Enhances Its Skin Penetration and Performance In Vitro While Reducing Its Toxicity In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 186
Author(s):  
Maria Natalia Calienni ◽  
Daniela Maza Vega ◽  
C. Facundo Temprana ◽  
María Cecilia Izquierdo ◽  
David E. Ybarra ◽  
...  
Keyword(s):  
Side Effects ◽  
Water Solubility ◽  
Polymeric Micelles ◽  
Skin Penetration ◽  
Distribution Volume ◽  
And Performance ◽  
Oral Doses ◽  
Advanced Basal Cell Carcinoma

Vismodegib is a first-in-class inhibitor for advanced basal cell carcinoma treatment. Its daily oral doses present a high distribution volume and several side effects. We evaluated its skin penetration loaded in diverse nanosystems as potential strategies to reduce side effects and drug quantities. Ultradeformable liposomes, ethosomes, colloidal liquid crystals, and dendrimers were able to transport Vismodegib to deep skin layers, while polymeric micelles failed at this. As lipidic systems were the most effective, we assessed the in vitro and in vivo toxicity of Vismodegib-loaded ultradeformable liposomes, apoptosis, and cellular uptake. Vismodegib emerges as a versatile drug that can be loaded in several delivery systems for topical application. These findings may be also useful for the consideration of topical delivery of other drugs with a low water solubility.

scholarly journals Fluorogenic Aptasensors with Small Molecules

Chemosensors ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 54
Author(s):  
Eun-Song Lee ◽  
Jeong Min Lee ◽  
Hea-Jin Kim ◽  
Young-Pil Kim
Keyword(s):  
Small Molecules ◽  
In Vitro Selection ◽  
Molecular Beacon ◽  
Future Directions ◽  
Rna Molecules ◽  
Amplification Process ◽  
Target Molecules ◽  
And Performance ◽  
Fluorescence Turn On

Aptamers are single-stranded DNA or RNA molecules that can be identified through an iterative in vitro selection–amplification process. Among them, fluorogenic aptamers in response to small molecules have been of great interest in biosensing and bioimaging due to their rapid fluorescence turn-on signals with high target specificity and low background noise. In this review, we report recent advances in fluorogenic aptasensors and their applications to in vitro diagnosis and cellular imaging. These aptasensors modulated by small molecules have been implemented in different modalities that include duplex or molecular beacon-type aptasensors, aptazymes, and fluorogen-activating aptamer reporters. We highlight the working principles, target molecules, modifications, and performance characteristics of fluorogenic aptasensors, and discuss their potential roles in the field of biosensor and bioimaging with future directions and challenges.

scholarly journals Biological nanoscale fluorescent probes: From structure and performance to bioimaging

2020 ◽  
Vol 39 (1) ◽  
pp. 209-221
Author(s):  
Jiafeng Wan ◽  
Xiaoyuan Zhang ◽  
Kai Zhang ◽  
Zhiqiang Su
Keyword(s):  
Fluorescent Probes ◽  
Organic Dyes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
High Sensitivity ◽  
Biological Imaging ◽  
Fluorescent Materials ◽  
And Performance

Abstract In recent years, nanomaterials have attracted lots of attention from researchers due to their unique properties. Nanometer fluorescent materials, such as organic dyes, semiconductor quantum dots (QDs), metal nano-clusters (MNCs), carbon dots (CDs), etc., are widely used in biological imaging due to their high sensitivity, short response time, and excellent accuracy. Nanometer fluorescent probes can not only perform in vitro imaging of organisms but also achieve in vivo imaging. This provides medical staff with great convenience in cancer treatment. Combined with contemporary medical methods, faster and more effective treatment of cancer is achievable. This article explains the response mechanism of three-nanometer fluorescent probes: the principle of induced electron transfer (PET), the principle of fluorescence resonance energy transfer (FRET), and the principle of intramolecular charge transfer (ICT), showing the semiconductor QDs, precious MNCs, and CDs. The excellent performance of the three kinds of nano fluorescent materials in biological imaging is highlighted, and the application of these three kinds of nano fluorescent probes in targeted biological imaging is also introduced. Nanometer fluorescent materials will show their significance in the field of biomedicine.

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