Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle

D’Ercole, Chiara; D'Angelo, Paolo; Ruggieri, Veronica; Proietti, Daisy; Virtanen, Laura; Parisi, Cristina; Riera, Carles Sánchez; Renzini, Alessandra; Macone, Alberto; Marzullo, Marta; Ciapponi, Laura; Bonvissuto, Davide; Sette, Claudio; Giordani, Lorenzo; Madaro, Luca

doi:10.1016/j.celrep.2022.111861

Cited by 19 publications

(26 citation statements)

References 55 publications

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“…In a longer-term perspective, translational research should aim at precising the dysregulation of the different anabolic and catabolic pathways according to the disease evolution and patient profile. New therapeutic targets could also emerge thanks to the use of large-scale multiomic approaches, such as spatial transcriptomics [ 223 ], allowing the spatiotemporal identification of new molecular targets in skeletal muscle health and disease.…”

Section: Discussionmentioning

confidence: 99%

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Henrot

Dupin

Schilfarth

et al. 2023

IJMS

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Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients’ samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future.

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Section: Discussionmentioning

confidence: 99%

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Henrot

Dupin

Schilfarth

et al. 2023

IJMS

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“…(I) Comparison between marker lists of each myofiber in this segmentation-based analysis (Hsu) and two previous single nucleus RNA sequencing studies [7, 8], using a Venn Diagram constructed with DeepVenn [16]. …”

Section: Resultsmentioning

confidence: 99%

“…Markers are compared with published marker lists for non-myelinating and myelinating Schwann cells [27] and terminal Schwann cells [30] (L). Top 20 significant genes were included in the DeepVenn [16] analysis. These genes were also plotted onto the magnified NMJ space (K), which shows geometry similar to typical NMJ structure (J).…”

Section: Resultsmentioning

confidence: 99%

“…myofiber segmented dataset and hexagonal dataset) was presented as SCT-normalized value, while spatial gene expression plot on raw coordinate histological plane was based on the raw gene expression data. For Area-proportional Venn diagrams were made using DeepVenn [16]. Overlapping hexagonal grid were generated to allow for multiscale sliding windows analysis [20, 23].…”

Section: Methodsmentioning

confidence: 99%

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High-Resolution Spatial Transcriptomic Atlas of Mouse Soleus Muscle: Unveiling Single Cell and Subcellular Heterogeneity in Health and Denervation

Hsu,

Ruiz,

Hwang

et al. 2024

Preprint

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Skeletal muscle is essential for both movement and metabolic processes, characterized by a complex and ordered structure. Despite its importance, a detailed spatial map of gene expression within muscle tissue has been challenging to achieve due to the limitations of existing technologies, which struggle to provide high-resolution views. In this study, we leverage the Seq-Scope technique, an innovative method that allows for the observation of the entire transcriptome at an unprecedented submicron spatial resolution. By applying this technique to the mouse soleus muscle, we analyze and compare the gene expression profiles in both healthy conditions and following denervation, a process that mimics aspects of muscle aging. Our approach reveals detailed characteristics of muscle fibers, other cell types present within the muscle, and specific subcellular structures such as the postsynaptic nuclei at neuromuscular junctions, hybrid muscle fibers, and areas of localized expression of genes responsive to muscle injury, along with their histological context. The findings of this research significantly enhance our understanding of the diversity within the muscle cell transcriptome and its variation in response to denervation, a key factor in the decline of muscle function with age. This breakthrough in spatial transcriptomics not only deepens our knowledge of muscle biology but also sets the stage for the development of new therapeutic strategies aimed at mitigating the effects of aging on muscle health, thereby offering a more comprehensive insight into the mechanisms of muscle maintenance and degeneration in the context of aging and disease.

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“…The underlying reason for such vast slow/fast-fiber type independent heterogeneity amongst fibers is not immediately obvious, though this could allude to a specialized spa-al organiza-on within a muscle fascicle to enable an op-mal response to specific forces and loads 63 , or specialized cellular or organ communica-on with other cell types within the muscle microenvironment [64][65][66] . Indeed, ribosomal specializa-on (via paralog subs-tu-on of RPL3 and RPL3L) has been implicated in skeletal muscle hypertrophy 67 .…”

Section: Discussionmentioning

confidence: 99%

Human Skeletal Muscle Fiber Heterogeneity Beyond Myosin Heavy Chains

Moreno-Justicia,

Van der Stede,

Stocks

et al. 2023

Preprint

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Skeletal muscle is an inherently heterogenous tissue comprised primarily of myofibers, which are historically classified into three distinct fiber types in humans: one “slow” (type 1) and two “fast” (type 2A and type 2X), delineated by the expression of myosin heavy chain isoforms (MYHs). However, whether discrete fiber types exist or whether fiber heterogeneity reflects a continuum remains unclear. Furthermore, whether MYHs are the main classifiers of skeletal muscle fibers has not been examined in an unbiased manner. Through the development and application of novel transcriptomic and proteomic workflows, applied to 1050 and 1038 single muscle fibers from humanvastus lateralis, respectively, we show that MYHs are not the principal drivers of skeletal muscle fiber heterogeneity. Instead, ribosomal specialization drives the majority of variance between skeletal muscle fibers in a continual fashion, independent of slow/fast fiber type. Furthermore, whilst slow and fast fiber clusters can be identified, described by their contractile and metabolic profiles, our data challenge the concept that type 2X are phenotypically distinct from other fast fibers at an omics level. Moreover, MYH-based classifications do not adequately describe the phenotype of skeletal muscle fibers in one of the most common genetic muscle diseases, nemaline myopathy. Our data question the currently accepted model of multiple distinct fiber types based on the expression of MYHs in humans and identifies ribosomal specialization as a major driver of skeletal muscle heterogeneity, opening a new field of research within skeletal muscle physiology.Abstract Figure

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Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle

Cited by 19 publications

References 55 publications

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

High-Resolution Spatial Transcriptomic Atlas of Mouse Soleus Muscle: Unveiling Single Cell and Subcellular Heterogeneity in Health and Denervation

Human Skeletal Muscle Fiber Heterogeneity Beyond Myosin Heavy Chains

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