The Need for Standardized Assessment of Muscle Quality in Skeletal Muscle Function Deficit and Other Aging-Related Muscle Dysfunctions: A Symposium Report

A growing body of scientific literature suggests that not only changes in skeletal muscle mass, but also other factors underpinning muscle quality, play a role in the decline in skeletal muscle function and impaired mobility associated with aging. A symposium on muscle quality and the need for standardized assessment was held on April 28, 2016 at the International Conference on Frailty and Sarcopenia Research in Philadelphia, Pennsylvania. The purpose of this symposium was to provide a venue for basic science and clinical researchers and expert clinicians to discuss muscle quality in the context of skeletal muscle function deficit and other aging-related muscle dysfunctions. The present article provides an expanded introduction concerning the emerging definitions of muscle quality and a potential framework for scientific inquiry within the field. Changes in muscle tissue composition, based on excessive levels of inter- and intra-muscular adipose tissue and intramyocellular lipids, have been found to adversely impact metabolism and peak force generation. However, methods to easily and rapidly assess muscle tissue composition in multiple clinical settings and with minimal patient burden are needed. Diagnostic ultrasound and other assessment methods continue to be developed for characterizing muscle pathology, and enhanced sonography using sensors to provide user feedback and improve reliability is currently the subject of ongoing investigation and development. In addition, measures of relative muscle force such as specific force or grip strength adjusted for body size have been proposed as methods to assess changes in muscle quality. Furthermore, performance-based assessments of muscle power via timed tests of function and body size estimates, are associated with lower extremity muscle strength may be responsive to age-related changes in muscle quality. Future aims include reaching consensus on the definition and standardized assessments of muscle quality, and providing recommendations to address critical clinical and technology research gaps within the field

Role of radiologic imaging in genetic and acquired neuromuscular disorders

Great technologic and clinical progress have been made in the last two decades in identifying genetic defects of several neuromuscular diseases, as Spinal Muscular Atrophy, genetic muscular dystrophies and other genetic myopathies. The diagnosis is usually challenging, due to great variability in genetic abnormalities and clinical phenotypes and the poor specificity of complementary analyses, i.e., serum creatine kinase (CK) and electrophysiology. Muscle biopsy represents the gold standard for the diagnosis of genetic neuromuscular diseases, but clinical imaging of muscle tissue is an important diagnostic tool to identify and quantifyies muscle damage. Radiologic imaging is, indeed, increasingly used as a diagnostic tool to describe patterns and the extent of muscle involvement, thanks to modern techniques that enable to definethe definition of degrees of muscle atrophy and changes in connective tissue. They usually grade the severity of the disease process with greater accuracy than clinical scores. Clinical imaging is more than complementary to perform muscle biopsy, especially as ultrasound scans are often mandatory to identify the muscle to be biopsied. We will here detail and provideWe will herein provide detailed examples of the radiologic methods that can be used in genetic and acquired neuromuscular disorders, stressing pros and cons

Automatic signal and image-based assessments of spinal cord injury and treatments.

Spinal cord injury (SCI) is one of the most common sources of motor disabilities in humans that often deeply impact the quality of life in individuals with severe and chronic SCI. In this dissertation, we have developed advanced engineering tools to address three distinct problems that researchers, clinicians and patients are facing in SCI research. Particularly, we have proposed a fully automated stochastic framework to quantify the effects of SCI on muscle size and adipose tissue distribution in skeletal muscles by volumetric segmentation of 3-D MRI scans in individuals with chronic SCI as well as non-disabled individuals. We also developed a novel framework for robust and automatic activation detection, feature extraction and visualization of the spinal cord epidural stimulation (scES) effects across a high number of scES parameters to build individualized-maps of muscle recruitment patterns of scES. Finally, in the last part of this dissertation, we introduced an EMG time-frequency analysis framework that implements EMG spectral analysis and machine learning tools to characterize EMG patterns resulting in independent or assisted standing enabled by scES, and identify the stimulation parameters that promote muscle activation patterns more effective for standing. The neurotechnological advancements proposed in this dissertation have greatly benefited SCI research by accelerating the efforts to quantify the effects of SCI on muscle size and functionality, expanding the knowledge regarding the neurophysiological mechanisms involved in re-enabling motor function with epidural stimulation and the selection of stimulation parameters and helping the patients with complete paralysis to achieve faster motor recovery

Semi-Supervised Deep Learning for Multi-Tissue Segmentation from Multi-Contrast MRI

Segmentation of thigh tissues (muscle, fat, inter-muscular adipose tissue (IMAT), bone, and bone marrow) from magnetic resonance imaging (MRI) scans is useful for clinical and research investigations in various conditions such as aging, diabetes mellitus, obesity, metabolic syndrome, and their associated comorbidities. Towards a fully automated, robust, and precise quantification of thigh tissues, herein we designed a novel semi-supervised segmentation algorithm based on deep network architectures. Built upon Tiramisu segmentation engine, our proposed deep networks use variational and specially designed targeted dropouts for faster and robust convergence, and utilize multi-contrast MRI scans as input data. In our experiments, we have used 150 scans from 50 distinct subjects from the Baltimore Longitudinal Study of Aging (BLSA). The proposed system made use of both labeled and unlabeled data with high efficacy for training, and outperformed the current state-of-the-art methods with dice scores of 97.52%, 94.61%, 80.14%, 95.93%, and 96.83% for muscle, fat, IMAT, bone, and bone marrow tissues, respectively. Our results indicate that the proposed system can be useful for clinical research studies where volumetric and distributional tissue quantification is pivotal and labeling is a significant issue. To the best of our knowledge, the proposed system is the first attempt at multi-tissue segmentation using a single end-to-end semi-supervised deep learning framework for multi-contrast thigh MRI scans.Comment: 20 pages, 9 figures, Journal of Signal Processing System

Skeletal Muscle Impairments in People with Diabetes and Peripheral Neuropathy

Abstract of the Dissertation Skeletal Muscle Impairments in People with Diabetes and Peripheral Neuropathy by Lori Jeanne Tuttle Doctor of Philosophy in Movement Science Washington University in St. Louis, 2011 Dr. Michael J. Mueller, Chairperson Diabetes mellitus: DM) is a chronic disease that affects almost 24 million people and has large socioeconomic costs. Of these 24 million people, 60-70 % will develop some form of nervous system impairment, including peripheral neuropathy: PN). It is important to understand muscle structure and impairments in people with DM+PN in order to determine appropriate interventions to limit the disability that is associated with DM+PN. The objectives of this research are to describe skeletal muscle structure in people with DM+PN, to determine whether neuropathic muscle structure and composition are associated with movement impairments and functional limitations, and whether neuropathic muscle can be modulated by activity level and/or an exercise intervention. In Chapter 2, we examine whether intermuscular adipose tissue: IMAT) volumes are different between groups with DM, DM+PN, and a group without DM or PN: NoDMPN). We report that there is no difference in IMAT volumes in these groups, but that increased IMAT is associated with poorer physical performance and the DM+PN group had the lowest measures of physical performance. In Chapter 3, we examine whether activity level in people with DM+PN is associated with IMAT. We report that activity level is inversely associated with IMAT volumes. In Chapter 4, we examine whether an exercise intervention for people with DM+PN is able to improve function and change IMAT and muscle volumes. We report that our duration-based exercise program was successful in increasing 6 minute walk distance, but there was no change in IMAT or muscle volumes. In Chapter 5, we provide a case report detailing an exercise intervention for a specific individual with DM+PN who was able to increase his average activity level and shows improvement in muscle performance and physical function. Overall, our results suggest that people with DM+PN have lower levels of physical performance than their peers and increased IMAT is associated with poor physical performance. Increased activity levels are associated with decreased IMAT volume. People with DM+PN are able to safely increase their walking distance following an exercise intervention, but we did not see a change in muscle composition. Additional research is needed to determine the specific roles of IMAT in skeletal muscle and function

Association of Thigh Muscle Strength with Texture Features Based on Proton Density Fat Fraction Maps Derived from Chemical Shift Encoding-Based Water-Fat MRI

Purpose: Based on conventional and quantitative magnetic resonance imaging (MRI), texture analysis (TA) has shown encouraging results as a biomarker for tissue structure. Chemical shift encoding-based water–fat MRI (CSE-MRI)-derived proton density fat fraction (PDFF) of thigh muscles has been associated with musculoskeletal, metabolic, and neuromuscular disorders and was demonstrated to predict muscle strength. The purpose of this study was to investigate PDFF-based TA of thigh muscles as a predictor of thigh muscle strength in comparison to mean PDFF. Methods: 30 healthy subjects (age = 30 ± 6 years; 15 females) underwent CSE-MRI of the lumbar spine at 3T, using a six-echo 3D spoiled gradient echo sequence. Quadriceps (EXT) and ischiocrural (FLEX) muscles were segmented to extract mean PDFF and texture features. Muscle flexion and extension strength were measured with an isokinetic dynamometer. Results: Of the eleven extracted texture features, Variance(global) showed the highest significant correlation with extension strength (p 2adj = 0.712), and Correlation showed the highest significant correlation with flexion strength (p = 0.016, R2adj = 0.658). Multivariate linear regression models identified Variance(global) and sex, but not PDFF, as significant predictors of extension strength (R2adj = 0.709; p 2adj = 0.674; p < 0.001). Conclusions: Prediction of quadriceps muscle strength can be improved beyond mean PDFF by means of TA, indicating the capability to quantify muscular fat infiltration patterns

EFFECTS OF ACUTE POSTURAL CHANGE ON MID-THIGH CROSS-SECTIONAL AREA AS MEASURED BY COMPUTED TOMOGRAPHY

Fluid shifts resulting from postural change present a potential source of error when assessing the CSA of limb tissue using CT. In the present study mid-thigh axial scans of 13 older women were obtained at 5, 10, and 15 minutes of supine rest. Scans were analyzed for changes in CSA of subcutaneous fat(SF), low density muscle(LDM) and normal density muscle(NDM) tissue. A significant decrease was found in NDM CSA at 15 minutes (2.3 ± 0.8, 1.6%, P&lt;0.05) with no change in LDM or SF CSA between any time interval The current study suggests that the potential measurement error associated with fluid shifting out of the tissues can be minimized when baseline and follow-up CT-derived images of mid-thigh CSA are obtained within the first 10 minutes the subject assumes the supine position and that the CSA of NDM and LDM may be affected differently by loss of hydrostatic pressure

ROLE OF FAT CONTENT ON THE STRUCTURE AND FUNCTION OF HUMAN SKELETAL MUSCLE

Muscle size does not fully explain variations in muscle strength. Fat content has been implicated in muscle weakness, though this relationship remains unclear. The relationship between fat and strength may vary between scales (e.g., cellular, organ, and organism). The goal of this dissertation was to clarify the role of fat in the structure and function of muscle using in vitro and in vivo techniques across multiple scales in adults 21-45 years old. Study 1 tested the agreement of intramyocellular lipid (IMCL) content between oil red o (ORO) and magnetic resonance spectroscopy (MRS) techniques. These measures of IMCL were also compared to measures of quadriceps fat content (fat fraction, FF) by magnetic resonance imaging (MRI). Results showed that fat by ORO, MRS, nor MRI were related. This suggests that extracellular lipid contributes to IMCL by MRS, and that fat is not a primarily storage location within muscle cells. Study 2 quantified the relationships between FF, architecture, and strength in vivo using MRI, diffusion tensor imaging (DTI), and isokinetic dynamometry. There was a relationship between FF and fascicle length. However, FF was not related to measures of muscle strength. This suggests that fat may be related to shorter fascicles, but does not impair maximal strength. Muscle curvature and pennation angle were related to muscle strength, suggesting that they may be additional contributors to strength. Study 3 compared measures of single fiber function to whole muscle strength. The relationship between IMCL and single fiber function was also quantified. Measures of IMCL, FF, and BMI were not related, suggesting that IMCL does not contribute to fat t measured at the whole muscle or whole body levels. Measures of IMCL were also not related to single fiber function, indicating that greater levels of lipid accumulation may be necessary for fat-induced impairment of single fiber function. Collectively, the findings of this dissertation indicate that fat and mechanical function must be evaluated at the same anatomical scale for clear interpretations of their relationship. Additionally, this work suggests that fat may have a relationship with muscle structure, but not does have a direct effect on strength

Non-invasive evaluation of murine models for genetic muscle diseases

Novel therapeutic approaches are being introduced for genetic muscle diseases such as muscle dystrophies and congenital myopathies, all of them having remained without cure so far. These recent developments have motivated a renewed and augmented interest in non-invasive methods for muscle characterization and monitoring, particularly during and after therapeutic intervention. In this context, animal models are essential to better understand the disease mechanisms and to test new therapies. Recently, significant advances in the non-invasive evaluation of mouse models for genetic muscle diseases have been achieved. Nevertheless, there were still several mouse strains not characterized non-invasively, and it was necessary to develop sensitive methods to identify subtle alterations in the murine affected muscle. The purpose of this thesis was to apply non-invasive techniques in the study of murine models for genetic muscle diseases with variable phenotypes. Three mouse models for muscle dystrophy (mdx, Large_myd, mdx/Large_myd) and one mouse model for congenital myopathy (KI-Dnm2_R465W) were studied with Nuclear Magnetic Resonance (NMR) methods. Two dystrophic strains (Large_myd, mdx/Large_myd) and normal mice after injury were studied through micro-Computed Tomography (micro-CT). On NMR, all affected mouse strains presented increased muscle T2, which could be related to variable features in the histological evaluation, including necrosis and inflammation, but also to clusters of fibers under regeneration or with altered cytoarchitecture. The combination of NMR and texture analyses allowed the unambiguous differential identification of all the dystrophic strains, although it was not feasible when comparing the muscle T2 measurements only. Mdx mice showed functional and morphological alterations of vascular network. In the KI-Dnm2_R465W mice, a pilot study revealed tendencies of functional impairment. Finally, micro-CT images were unable to detect differences in muscle´s content in dystrophic mice. Altogether, these results not only increased the number of murine models for genetic muscle diseases non-invasively characterized, it also demonstrated some degree of specificity of the imaging anomalies, as revealed by texture analysis. It also showed that non-invasive NMR methods can be sensitive enough to identify subtle alterations in murine muscle phenotype, even in early stages. This thesis was developed under an international joint supervision between France and Brazil, and comprised an important transfer of technology, with the first non-invasive studies of murine muscles performed in Brazil.De nouvelles options thérapeutiques sont en cours d'introduction pour les maladies musculaires génétiques telles que les dystrophies musculaires et les myopathies congénitales, maladies jusque là sans traitement causal. Ces développements récents ont suscité un intérêt renouvelé et croissant pour les méthodes atraumatiques en vue de caractériser et de suivre les muscles atteints, en particulier pendant et après une intervention thérapeutique. Dans ce contexte, les modèles animaux sont essentiels pour mieux comprendre les mécanismes des maladies et pour tester des nouvelles thérapies. Récemment, il y a eu des avancées significatives dans l'évaluation atraumatique de modèles murins de maladies musculaires génétiques. Néanmoins, nombre de lignées de souris n'ont pas encore été caractérisées de façon atraumatique et il reste à mettre au point des méthodes plus sensibles pour identifier précocement des altérations subtiles dans le muscle des souris malades. L'objectif de cette thèse est d'appliquer des techniques atraumatiques innovantes à l'étude du muscle de modèles murins de maladies musculaires génétiques avec des phénotypes variés. Trois lignées de souris modèles de dystrophies musculaires (mdx, Large_myd et mdx/Large_myd) et une lignée de souris modèle de la myopathie congénitale (KI-Dnm2_R465W) ont été étudiées par des méthodes de Résonance Magnétique Nucléaire (RMN). Deux lignées dystrophiques (Large_myd et mdx/Large_myd) plus des souris normales après une blessure ont été étudiées par micro-tomographie (micro-CT). En RMN, toutes les souches de souris affectées ont présenté un T2 musculaire augmenté, en relation avec une gamme d'anomalies histologiques, y comprises nécrose et inflammation, mais aussi des groupes de fibres en régénération ou des fibres avec altérations de l'architecture. Avec la combinaison de la RMN et de l'analyse de la texture, il a été possible d'identifier sans ambiguïté toutes les lignées dystrophiques, alors que la seule mesure du T2 ne permettait pas de les différencier. Les souris mdx ont présenté des altérations fonctionnelles et morphologiques du réseau vasculaire musculaire. Pour les souris KI-Dnm2_R465W, des études préliminaires ont révélé une tendance à développer des altérations fonctionnelles musculaires. Finalement, les images de micro-CT n'ont pas pu détecter des différences du contenu musculaire dans les souris dystrophiques. L'ensemble des résultats non seulement enrichit le panel de modèles murins de maladies génétiques musculaires caractérisés de manière atraumatique, il révèle également un certain degré de spécificité des anomalies dans l'imagerie, comme l'a montré l'analyse de texture. Les résultats démontrent aussi que des méthodes de RMN non-invasives peuvent être assez sensibles pour identifier des altérations subtiles dans le phénotype musculaire murin, même à des stades précoces. Cette thèse a été développée dans le cadre d'une co-tutelle internationale entre la France et le Brésil, et elle a comporté un important transfert de compétence, qui a permis de réaliser les premières explorations atraumatiques du muscle murin effectuées au Brésil

Sarcopenia in the Context of Skeletal Muscle Function Deficit (SMFD)

Evidence shows that not only changes in skeletal muscle mass but changes in strength and other factors underpinning muscle quality play a role in muscle function decline and impaired mobility associated with aging. Changes in both strength and quality may precede loss of muscle mass. Skeletal muscle function deficit (SMFD) is a terminology that embraces this evolving conceptualization of sarcopenia and age-related muscle dysfunctions. This chapter provides a discussion on sarcopenia in the context of SMFD, including operational definitions and methodological challenges associated with their establishment; integration of muscle quality into SMFD; efforts to identify diagnostic cutoff values for low muscle mass and weakness and their predictive validity to mobility disability; need for standardized muscle quality assessment; clinical and public health relevance and research opportunities. Changes in muscle composition, based on excessive levels of inter- and intramuscular or intramyocellular fat are striking features increasingly addressed in the literature, found to affect muscle metabolism and peak force generation. Methods to easily and rapidly assess muscle composition in multiple clinical settings and with minimal patient burden are needed. Further characterization of SMFD should emphasize integration of muscle quality and factors behind changes in quality, as well as associated clinical and research implications