Botulinum Toxin Induced Atrophy: An Uncharted Territory

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Abstract

Botulinum neurotoxins (BoNTs) produce local chemo-denervation by cleaving soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins. Botulinum neurotoxins are therapeutically indicated in several neurological disorders and have been in use for three decades. The long-term efficacy, safety, and side effects of BoNTs have been well documented in the literature. However, the development of muscle atrophy following chronic exposure to BoNTs has not received sufficient attention. Muscle atrophy is not only cosmetically distressing, but also has an impact on future injections. An extensive literature search was conducted on atrophy and mechanisms of atrophy. Five hundred and four relevant articles in the English language were reviewed. This review revealed the surprising lack of documentation of atrophy within the literature. In addition, as demonstrated in this review, the mechanisms and the clinical factors that may lead to atrophy have also been poorly studied. However, even with this limited information it is possible to indicate factors that could modify the clinical approach to botulinum toxin injections. This review highlights the need for further study of atrophy following BoNT injections.

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Muscle type and fiber type specificity in muscle wasting.

Stefano Ciciliot, Alberto Rossi, Kenneth A. Dyar … (2013)

Muscle wasting occurs in a variety of conditions, including both genetic diseases, such as muscular dystrophies, and acquired disorders, ranging from muscle disuse to cancer cachexia, from heart failure to aging sarcopenia. In most of these conditions, the loss of muscle tissue is not homogeneous, but involves specific muscle groups, for example Duchenne muscular dystrophy affects most body muscles but spares extraocular muscles, and other dystrophies affect selectively proximal or distal limb muscles. In addition, muscle atrophy can affect specific fiber types, involving predominantly slow type 1 or fast type 2 muscle fibers, and is frequently accompanied by a slow-to-fast or fast-to-slow fiber type shift. For example, muscle disuse, such as spinal cord injury, causes type 1 fiber atrophy with a slow-to-fast fiber type shift, whereas cancer cachexia leads to preferential atrophy of type 2 fibers with a fast-to-slow fiber type shift. The identification of the signaling pathways responsible for the differential response of muscles types and fiber types can lead to a better understanding of the pathogenesis of muscle wasting and to the design of therapeutic interventions appropriate for the specific disorders. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. Copyright © 2013 Elsevier Ltd. All rights reserved.

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A systematic review: efficacy of botulinum toxin in walking and quality of life in post-stroke lower limb spasticity

Anupam Gupta, Wing Chu, Stuart Howell … (2018)

Background Improved walking is one of the highest priorities in people living with stroke. Post-stroke lower limb spasticity (PSLLS) impedes walking and quality of life (QOL). The understanding of the evidence of improved walking and QOL following botulinum toxin (BoNTA) injection is not clear. We performed a systematic review of the randomized control trials (RCT) to evaluate the effectiveness of BoNTA injection on walking and QOL in PSLLS. Methods We searched PubMed, Web of Science, Embase, CINAHL, ProQuest Thesis and Dissertation checks, Google Scholar, WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, Cochrane, and ANZ and EU Clinical Trials Register for RCTs looking at improvement in walking and QOL following injection of BoNTA in PSLLS. The original search was carried out prior to 16 September 2015. We conducted an additional verifying search on CINHAL, EMBASE, and MEDLINE (via PubMed) from 16 September 2015 to 6 June 2017 using the same clauses as the previous search. Methodological quality of the individual studies was critically appraised using Joanna Briggs Institute’s instrument. Only placebo-controlled RCTs looking at improvement in walking and QOL were included in the review. Results Of 2026 records, we found 107 full-text records. Amongst them, we found five RCTs qualifying our criteria. No new trials were found from the verifying search. Two independent reviewers assessed methodological validity prior to inclusion in the review using Joanna Briggs Institute’s appraisal instrument. Two studies reported significant improvement in gait velocity (p = 0.020) and < 0.05, respectively. One study showed significant improvement in 2-min-walking distance (p < 0.05). QOL was recorded in one study without any significant improvement. Meta-analysis of reviewed studies could not be performed because of different methods of assessing walking ability, small sample size with large confidence interval and issues such as lack of power calculations in some studies. Findings from our systematic and detailed study identify the need for a well-designed RCT to adequately investigate the issues highlighted. Conclusions This review could not conclude there was sufficient evidence to support or refute improvement on walking or QOL following BoNTA injection. Reasons for this are discussed, and methods for future RCTs are developed.

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Mitochondrial signaling contributes to disuse muscle atrophy.

Arif H. Demirel, Michael P. Wiggs, A. Demiroglu-Zergeroglu … (2012)

It is well established that long durations of bed rest, limb immobilization, or reduced activity in respiratory muscles during mechanical ventilation results in skeletal muscle atrophy in humans and other animals. The idea that mitochondrial damage/dysfunction contributes to disuse muscle atrophy originated over 40 years ago. These early studies were largely descriptive and did not provide unequivocal evidence that mitochondria play a primary role in disuse muscle atrophy. However, recent experiments have provided direct evidence connecting mitochondrial dysfunction to muscle atrophy. Numerous studies have described changes in mitochondria shape, number, and function in skeletal muscles exposed to prolonged periods of inactivity. Furthermore, recent evidence indicates that increased mitochondrial ROS production plays a key signaling role in both immobilization-induced limb muscle atrophy and diaphragmatic atrophy occurring during prolonged mechanical ventilation. Moreover, new evidence reveals that, during denervation-induced muscle atrophy, increased mitochondrial fragmentation due to fission is a required signaling event that activates the AMPK-FoxO3 signaling axis, which induces the expression of atrophy genes, protein breakdown, and ultimately muscle atrophy. Collectively, these findings highlight the importance of future research to better understand the mitochondrial signaling mechanisms that contribute to disuse muscle atrophy and to develop novel therapeutic interventions for prevention of inactivity-induced skeletal muscle atrophy.

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Journal

Journal ID (nlm-ta): Toxins (Basel)

Journal ID (iso-abbrev): Toxins (Basel)

Journal ID (publisher-id): toxins

Title: Toxins

Publisher: MDPI

ISSN (Electronic): 2072-6651

Publication date (Electronic): 02 August 2018

Publication date Collection: August 2018

Volume: 10

Issue: 8

Electronic Location Identifier: 313

Affiliations

[1 ]Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, 339 Windermere Road, A10-026, London, ON N6A 5A5, Canada; mehri.salari@ 123456gmail.com (M.S.); soumya0325@ 123456gmail.com (S.S.)

[2 ]Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, 19839-63113 Tehran, Iran

Author notes

[* ]Correspondence: mandar.jog@ 123456lhsc.on.ca ; Tel.: +1-519-663-3814

[†]

These authors contributed equally to the study and share first authorship.

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Mehri Salari https://orcid.org/0000-0001-7102-821X

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Publisher ID: toxins-10-00313

DOI: 10.3390/toxins10080313

PMC ID: 6115806

PubMed ID: 30072597

SO-VID: 6f01c449-b2c0-4039-95fd-63ba9da6f39e

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 04 July 2018

Date accepted : 31 July 2018

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Botulinum Toxin Induced Atrophy: An Uncharted Territory

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Most cited references 78

Muscle type and fiber type specificity in muscle wasting.

A systematic review: efficacy of botulinum toxin in walking and quality of life in post-stroke lower limb spasticity

Mitochondrial signaling contributes to disuse muscle atrophy.

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Cited by 11

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