Muscle Atrophy Classification: The Need for a Pathway-Driven Approach

: It is well known that muscles can waste away (atrophy) due to a lack of physical activity. Muscle wasting commonly presents with reduced muscle strength and an impaired ability to perform daily tasks. Several studies have attempted to categorize muscle atrophy into three main subgroups: physiologic, pathologic, and neurogenic atrophy. Physiologic atrophy is caused by the general underuse of skeletal muscle (e.g., bedridden). Pathologic atrophy is characterized as the loss of stimulus to a specific region (e.g. aging). Neurogenic atrophy results from damage to the nerve innervating a muscle (e.g. SMA, GBS). Mechanisms have been elucidated for many of these pathways (e.g., ubiquitin-proteasome system, NF-κB, etc.). However, many causes of muscle atrophy (e.g., burns, arthritis, etc.) operate through unelucidated signaling cascades. Therefore, this review highlights the underlying mechanisms of each subtype of muscle atrophy while emphasizing the need for additional research in properly classifying and identifying muscle atrophy.

AB1237 Diagnostic value of proteasomal and autophagic markers in muscular diseases

Background:Deficient cellular degradation pathways such as autophagy and the ubiquitin proteasome system (UPS) show a correlation with the onset of neurodegenerative diseases. Especially immune-mediated inflammatory myopathies often show therapy-resistant phenotypes with medical need for further understanding of pathogenesis und possible treatment.Objectives:The aim of this work was to study an association of these two degradation pathways in a large group of different muscle entities and to examine a possible influence in the pathogenesis of the investigated muscle diseases. Furthermore, a potential benefit in diagnostics was studied using factors such as ubiquitin, p62, NBR1 and LC3 and their role as adapter molecules.Methods:We examined ubiquitin, p62, NBR1 and LC3 on muscle biopsies from patients with the diagnosis of s-IBM, dermato- and polymyositis, muscular dystrophy, neurogenic atrophy, myotonic dystrophy type II (PROMM) and metabolic myopathies such as Pompe and McArdle disease. Immunohistochemical single and double stainings as well as immunofluorescence stainings were performed on cryosections. Furthermore, Western blot analysis was performed. The use of a histological score, defined as the product of the frequency of positive fibres and staining intensity, was used to investigate possible differences between the diseases in the expression of the investigated factors.Results:Especially in s-IBM, myofibrillar myopathies and Pompe disease, proteasomal and autophagic markers were detected. On the other hand, neurogenic atrophy, McArdle disease and the majority of the myotonic dystrophies type II showed no positive signals, except for p62, which was detected especially in internalized nuclei and regenerative fibres. Overall, in all entities in regenerative and necrotic as well as in atrophic fibres, a positive staining for ubiquitin, p62, NBR1 and LC3 could be shown. Dermatomyositis showed a moderate immunoreactivity for p62 and NBR1 in the area of the perifascicular atrophy. Polymyositis showed a strong endomysial reaction in the area of the attacked muscle fibres, especially in the area of the lymphocytic infiltrates. The histological score showed that ubiquitin was significantly higher in s-IBM than in polymyositis. NBR1 was significantly higher in s-IBM than in dermatomyositis and muscular dystrophies. LC3 and p62 showed a significantly higher level in s-IBM as compared to dermatomyositis and polymyositis. Except for NBR1, a positive correlation of autophagic and proteasomal markers was shown in dermatomyositis. There was also a positive correlation between LC3 and ubiquitin in polymyositis. Using multivariate analysis and recursive partitioning, we could show a predictability of the diagnosis of s-IBM with a LC3 score above 3. On the other hand, a value below 3 excluded the diagnosis of s-IBM.Conclusion:In particular, s-IBM, myofibrillar myopathies and Pompe disease showed a possible involvement disturbed proteasomal and autophagic degradation pathways in their pathogenesis. In addition, p62 and NBR1 seemed to have an important role in the immune response. Furthermore, the altered autophagic and proteasomal degradation pathways may be involved in ageing processes, sarcopenia and disease. In particular, LC3 seems to be suitable as a screening marker to recognize an idiopathic inflammatory myopathy. The other markers, such as p62, LC3, and NBR1, would be able to distinguish between the subgroups of idiopathic inflammatory myopathies. Therefore, LC3 could be included as a marker in the routine of neuropathological diagnostics. Further studies are needed to fully understand the role of proteasomal and autophagic factors in possible immune suppressive and immune modulatory therapies and to assess possible side effects.Disclosure of Interests:Ulrich Drott: None declared, Patrick Harter: None declared, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Michel Mittelbronn: None declared

Denervation of the Tensor Veli Palatini Muscle and Effusion in the Tympanic Cavity

An English springer spaniel was presented for right-sided atrophy of the muscles of mastication, analgesia and paralysis of the face, and vestibular dysfunction. Neurological signs were consistent with a lesion involving the pons and rostral medulla resulting in deficits in the function of the trigeminal, facial, and vestibular nerves. MRI disclosed a right-sided extraparenchymal mass consistent with a trigeminal nerve sheath neoplasm that was compressing and invading the pons and medulla. Atrophy of the muscles of mastication, innervated by the trigeminal nerve, was also observed on MRI. Additionally, effusion was present in the ipsilateral tympanic cavity. Gross and microscopic evaluation of the right tensor veli palatini muscle (TVPM) was consistent with neurogenic atrophy. Effusion in the tympanic cavity was likely the result of an inability to open the auditory tube as a consequence of paralysis of the TVPM. Without the ability to open the auditory tube, gases present within the auditory tube and tympanic cavity may be absorbed, creating a negative pressure environment that leads to fluid transudation and effusion build up. To the authors' knowledge, this is the first report to document neurogenic atrophy of the TVPM with concurrent effusion in the ipsilateral tympanic cavity.