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Neuromuscular injuries and pharyngeal dysfunction in snorers and sleep apnea patients: a study on pathological changes in the human soft palate and its relationship with swallowing dysfunction
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. (Laboratory of Muscle Biology)
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obstructive sleep apnea (OSA) is a prevalent progressive sleep disorder with serious negative health consequences. Although several risk factors such as obesity can make an individual vulnerable to develop OSA, the pathophysiological mechanism for the collapse of the upper airway is unclear. Moreover, the etiology of the commonly occurring swallowing dysfunction in snorers and sleep apnea patients is not understood. In the light of this, we aimed to investigate whether muscle and nerve changes in upper airway contributes to pharyngeal dysfunction in snorers and sleep apnea patients.

Twenty-two patients (1 female, 21 males, mean age 45 years) undergoing soft palate surgery because of snoring and sleep apnea were included in the study. Ten healthy non-snoring males, mean age 38 years, were recruited as controls. Biopsies from the uvula were obtained from both patients and voluntary controls. Control autopsies from both uvula and palatopharyngeus muscles were taken post mortem from 6 previously healthy adult subjects (3 males, 3 females, mean age 52 years) and two male infants (age 4 months and 1.4 years). Overnight sleep registration and videoradiographic examinations of pharyngeal swallowing function were performed in both patients and voluntary controls.

Enzyme and immunohistochemistry and morphometric techniques were used to investigate cytoskeletal and membrane proteins desmin and dystrophin and two neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). The nerve fascicles in the soft palate were explored for changes in axon and Schwann cell density and for signs of axon regeneration. 

All patients were snores, and 14 patients had OSA with a mean apnea-hypopnea index 24, range 5-84. Sixteen of the 22 patients had swallowing dysfunction. None of the 10 voluntary controls had sleep apnea or swallowing dysfunction. In both controls and patients, a subgroup of muscle fibers in the soft palate lacked immunoreaction for desmin and the C-terminus of dystrophin, and these fibers were more common in patients than in controls (p<0.001). Moreover, muscle fibers with disorganized desmin were commonly observed in patients, but not in controls (p<0.001). Thus, overall, desmin abnormalities were significantly more frequent in patients (46 vs. 15%, p<0.001), and some of these fibers showed upregulation of BDNF. In addition, nerve fascicles from the soft palate of patients displayed lower density of axons (p<0.02) and a smaller area occupied by Schwann cells (p=0.001) compared to controls. The axon density within nerve fascicles as well as the cytoskeletal abnormalities in muscles correlated significantly with swallowing dysfunction (rs=0.50 and 0.76, respectively, p≤0.03).

To conclude, human soft palate muscles seem to be of a unique allotype. In the soft palate of snorers and sleep apnea patients, cytoskeletal myopathy and neuropathy were frequently observed, and these changes correlate significantly with pharyngeal swallowing dysfunction. The upregulation of BDNF in muscle fibers of patients may relate to a regenerative attempt after injury. Consequently, a disturbed sensorimotor function and muscle weakness may contribute to development and progression of swallowing dysfunction and OSA. Traumatic snoring vibrations and muscle overload are plausible causes of the neuromuscular injuries. 

Place, publisher, year, edition, pages
Umeå: Umeå University , 2018. , p. 48
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1948
Keywords [en]
Axons, BDNF, desmin, dystrophin, obstructive sleep apnea, OSA, pharyngeal function, muscle, myopathy, neuropathy, Schwann cells, swallowing dysfunction, upper airway
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology; Oto-Rhino-Laryngology; Pathology; molecular cell biology
Identifiers
URN: urn:nbn:se:umu:diva-146920ISBN: 978-91-7601-844-6 (print)OAI: oai:DiVA.org:umu-146920DiVA, id: diva2:1200372
Public defence
2018-05-18, Bio. A-206, Integrativ Medicinsk Biologi, Biologihuset, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2018-04-27 Created: 2018-04-24 Last updated: 2018-11-19Bibliographically approved
List of papers
1. Unique expression of cytoskeletal proteins in human soft palate muscles
Open this publication in new window or tab >>Unique expression of cytoskeletal proteins in human soft palate muscles
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2016 (English)In: Journal of Anatomy, ISSN 0021-8782, E-ISSN 1469-7580, Vol. 228, no 3, p. 487-494Article in journal (Refereed) Published
Abstract [en]

The human oropharyngeal muscles have a unique anatomy with diverse and intricate functions. To investigate if this specialization is also reflected in the cytoarchitecture of muscle fibers, intermediate filament proteins and the dystrophin-associated protein complex have been analyzed in two human palate muscles, musculus uvula (UV) and musculus palatopharyngeus (PP), with immunohistochenmical and morphological techniques. Human limb muscles were used as reference. The findings show that the soft palate muscle fibers have a cytoskeletal architecture that differs from the limb muscles. While all limb muscles showed immunoreaction for a panel of antibodies directed against different domains of cytoskeletal proteins desmin and dystrophin, a subpopulation of palate muscle fibers lacked or had a faint immunoreaction for desmin (UV 11.7% and PP 9.8%) and the C-terminal of the dystrophin molecule (UV 4.2% and PP 6.4%). The vast majority of these fibers expressed slow contractile protein myosin heavy chain I. Furthermore, an unusual staining pattern was also observed in these fibers for β-dystroglycan, caveolin-3 and neuronal nitric oxide synthase nNOS, which are all membrane-linking proteins associated with the dystrophin C-terminus. While the immunoreaction for nNOS was generally weak or absent, β-dystroglycan and caveolin-3 showed a stronger immunostaining. The absence or a low expression of cytoskeletal proteins otherwise considered ubiquitous and important for integration and contraction of muscle cells indicate a unique cytoarchitecture designed to meet the intricate demands of the upper airway muscles. It can be concluded that a subgroup of muscle fibers in the human soft palate appears to have special biomechanical properties, and their unique cytoarchitecture must be taken into account while assessing function and pathology in oropharyngeal muscles.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2016
Keywords
cytoskeleton, desmin, dystrophin, muscle fiber, palatopharyngeus, sleep apnea, soft palate, uvula
National Category
Otorhinolaryngology Physiology
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-115780 (URN)10.1111/joa.12417 (DOI)000373121100011 ()26597319 (PubMedID)2-s2.0-84948159654 (Scopus ID)
Funder
Swedish Heart Lung Foundation
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2023-03-24Bibliographically approved
2. Desmin and dystrophin myopathy in the upper airway of snoring and obstructive sleep apnea patients
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(English)Manuscript (preprint) (Other academic)
Keywords
Desmin, Dystrophin, pharyngeal muscles, swallowing and respiration, obstructive sleep apnea (OSA), myopathy
National Category
Cell and Molecular Biology
Research subject
Molecular Biology; Medical Cell Biology; Oto-Rhino-Laryngology; Pathology
Identifiers
urn:nbn:se:umu:diva-146911 (URN)
Funder
Swedish Heart Lung Foundation, Dnr 20110210, 20140339The Kempe Foundations
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-10-02
3. Upregulated expression of brain-derived neurotrophic factor in soft palate muscles of snorers and obstructive sleep apnea patients
Open this publication in new window or tab >>Upregulated expression of brain-derived neurotrophic factor in soft palate muscles of snorers and obstructive sleep apnea patients
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(English)Manuscript (preprint) (Other academic)
Keywords
Neurotrophins, brain-derived neurotrophic factor (BDNF), nerve-derived neurotrophic factor (NGF), snorers, obstructive sleep apnea, OSA, swallowing dysfunction, desmin, myopathy, neuropathy, neuromuscular injury, nerve, muscle, injury
National Category
Cell and Molecular Biology
Research subject
Oto-Rhino-Laryngology; Medical Cell Biology; Pathology
Identifiers
urn:nbn:se:umu:diva-146913 (URN)
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2019-09-20
4. Axon and Schwann cell degeneration in nerves of upper airway relates to pharyngeal dysfunction in snorers and sleep apnea patients
Open this publication in new window or tab >>Axon and Schwann cell degeneration in nerves of upper airway relates to pharyngeal dysfunction in snorers and sleep apnea patients
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(English)Manuscript (preprint) (Other academic)
Keywords
Nerve, Schwann cells, OSA, snorers, sleep apnea, neuromuscular damage
National Category
Neurosciences
Research subject
Medical Cell Biology; Oto-Rhino-Laryngology; Molecular Biology; Pathology
Identifiers
urn:nbn:se:umu:diva-146914 (URN)
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-10-02

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