The suction-modified Bergström needle muscle biopsy technique is safe and provides an adequate sample size for histologic, ultrastructural, DNA, and enzyme analysis.
Glucagon and insulin maintain blood glucose homeostasis and are used to treat hypoglycemia and hyperglycemia in diabetic patients, respectively. Whereas insulin is stable for weeks in its solution formulation, glucagon fibrillizes rapidly at the acidic pH required for solubility, and is therefore formulated as a lyophilized powder that is reconstituted in acidic solution immediately before use. Here we use solid-state NMR to determine the atomic-resolution structure of fibrils of synthetic human glucagon grown at pharmaceutically relevant low pH. Unexpectedly, two sets of chemical shifts are observed, indicating the coexistence of two β-strand conformations. Those two conformations have distinct water accessibilities and intermolecular contacts, indicating that they alternate and hydrogen-bond in an antiparallel fashion along the fibril axis. Two antiparallel β-sheets assemble with symmetric homodimer cross sections. This amyloid structure is stabilized by numerous aromatic, cation-π, polar and hydrophobic interactions, suggesting mutagenesis approaches to inhibit fibrillization to improve this important drug.
Peptides
and proteins commonly have complex structural landscapes
allowing for transformation into a wide array of species including
oligomers, aggregates, and fibrils. The formation of undesirable forms
including aggregates and fibrils poses serious risks from the perspective
of drug development and disease. Liraglutide, a GLP-1 agonist for
the treatment of diabetes, is a conjugated peptide that forms oligomers
that can be stabilized by pH and organic solvents. We have developed
an analytical toolkit to overcome challenges inherent to Liraglutide’s
conjugated acyl chain and probed the impact its oligomers have on
its physical stability. Our studies show that Liraglutide’s
oligomer states have significant and potentially detrimental impacts
on its propensity to aggregate and form fibrils as well as its potency.
Liraglutide delivered as a synthetic peptide is able to maintain its
oligomerization state in dried lyophilized powders, acting as a memory
effect from its synthetic process and purification. Through Liraglutide’s
oligomer memory effect, we demonstrate the importance and impact the
process for synthetic peptides can have on drug development spanning
from discovery to formulation development.
Fascioscapulohumeral Muscular Dystrophy (FSHD) is associated with the progressive loss of skeletal muscle mass and strength which results in significant functional impairments 1 . Ultimately, this severe muscle atrophy results in a loss of autonomy and a reduction in physical activity, exposing affected individuals to additional co-morbidities associated with a sedentary lifestyle. While exercise has been shown to be beneficial in other muscular dystrophies in both patient and animal models, specific data pertaining to FSHD is lacking. In addition, these studies are often performed on mixed patient groups and lack muscle biopsies to determine molecular outcomes 2-5 , making it difficult to draw specific conclusions on the effects of exercise on FSHD-affected skeletal muscle.Creatine monohydrate (Cr) supplementation has been widely studied in healthy populations but is also of benefit in certain ABSTRACT: Background: The FRG1-transgenic mouse displays muscle dysfunction and atrophy reminiscent of fascioscapulohumeral muscular dystrophy (FSHD) and could provide a model to determine potential therapeutic interventions. Methods: To determine if FRG1 mice benefit from treatments that improve muscle mass and function, mice were treated with creatine alone (Cr) or in combination with treadmill exercise (CrEX). Results: The CrEx treatment increased quadriceps weight, mitochondrial content (cytochome c oxidase (COX) activity, COX subunit one and four protein), and induced greater improvements in grip strength and rotarod fall speed. While Cr increased COX subunits one and four protein, no effect on muscle mass or performance was found. Since Cr resulted in no functional improvements, the benefits of CrEx may be mediated by exercise; however, the potential synergistic action of the combined treatment cannot be excluded. Conclusion: Treatment with CrEx attenuates atrophy and muscle dysfunction associated with FRG1 overexpression. These data suggest exercise and creatine supplementation may benefit individuals with FSHD.
RÉSUMÉ: Effets de la créatine et de l'exercice sur le muscle squelettique de souris transgéniques FRG1.Contexte : La souris transgénique FRG1 a une dysfonction et une atrophie musculaires qui ressemble à la dystrophie musculaire fascioscapulohumérale (DFSH), ce qui pourrait constituer un modèle pour l'identification d'avenues thérapeutiques. Méthode : Ces souris ont été traitées au moyen de la créatine seule (Cr) ou de la créatine et de l'exercice sur tapis roulant (CrEx) afin de déterminer si les souris FRG1 peuvent tirer un bénéfice des traitements qui améliorent la masse et la fonction musculaires. Résultats : Le traitement CrEx a augmenté le poids des quadriceps, le contenu mitochondrial (l'activité de la cytochrome c-oxydase (COX), la sous-unité 1 et quatre de la protéine COX), et a entraîné une plus importante amélioration de la force de préhension et de la vitesse de chute à l'épreuve du rotarod. Bien que la Cr ait augmenté les sous-unités 1 et 4 de Cox, elle n'a eu aucun effet sur la masse musculair...
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