Integrated genomic and proteomic analyses identify stimulus-dependent distinct molecular changes associated with skeletal muscle wasting
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ABSTRACT:
PROVIDER: PRJNA670942 | ENA |
REPOSITORIES: ENA
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Project description:Skeletal muscle wasting is a debilitating condition that occurs with aging and with many diseases, but the underlying mechanisms are incompletely understood. Previous work determined that common transcriptional changes occur in skeletal muscle during atrophy induced by different stimuli. However, whether this holds true at the proteome level remains largely unexplored. Here, we find that, contrary to this earlier model, distinct atrophic stimuli (corticosteroids, cancer, and aging) induce largely different mRNA and protein changes during muscle wasting in mice. Moreover, there is widespread transcriptome-proteome disconnect. Consequently, atrophy markers (atrogenes) identified in earlier microarray-based studies do not emerge from these proteomic surveys as the most relevantly associated with atrophy. Based on these analyses, we identify atrophy-regulated proteins (here defined as “atroproteins”) such as the myokine CCN1/Cyr61, which we find regulates myofiber type switching during sarcopenia. Altogether, these integrated analyses indicate that different catabolic stimuli induce muscle wasting via largely distinct mechanisms.
2021-10-22 | GSE159952 | GEO
Project description:Skeletal muscle atrophy is a debilitating condition that occurs with aging and disease but the underlying mechanisms are incompletely understood. Previous work determined that common transcriptional changes occur in muscle during atrophy induced by different stimuli. However, whether this holds true at the proteome level remains largely unexplored. Here, we find that, contrary to this earlier model, distinct atrophic stimuli (corticosteroids, cancer, and aging) induce largely different mRNA and protein changes during muscle atrophy in mice. Moreover, there is widespread transcriptome-proteome disconnect. Consequently, atrophy markers (atrogenes) identified in earlier microarray-based studies do not emerge from these proteomic surveys as the most relevantly associated with atrophy in all conditions. Rather, we identify proteins that are distinctly modulated by different types of atrophy (herein defined as “atroproteins”) such as the myokine CCN1/Cyr61, which regulates myofiber type switching during sarcopenia. Altogether, these integrated analyses indicate that different catabolic stimuli induce muscle atrophy via largely distinct mechanisms.
2022-02-22 | PXD027464 | Pride
Project description:Investigating muscle wasting in a murine model of cancer cachexia, we identified Oncostatin M (OSM) as a potential mediator of inflammatory responses in skeletal muscle. OSM is a member of the IL-6 family of cytokines and has crucial functions in cell growth, differentiation, and inflammation. Our results demonstrate that OSM induces muscle atrophy. To understand if its effect is specific or it is a general effect of IL6 family cytokines, primary myotubes were treated with OSM, IL6 and LIF for 48hrs. Our findings showed that OSM potently induces muscle wasting in differentiated myotubes.
2024-03-21 | GSE222208 | GEO
Project description:Skeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein we identified the transcriptional repressor protein, Forkhead box P1 (FoxP1), as a downstream target gene of FoxO1 whose skeletal muscle expression is elevated in multiple models of cancer cachexia and in patients with cancer who exhibit cachexia. Through generation of inducible skeletal muscle-specific FoxP1 over-expressing (FoxP1iSkmTg/Tg) mice, we demonstrate that FoxP1 upregulation is sufficient to induce features of cachexia, including body and skeletal muscle wasting characterized by reduced muscle fiber cross-sectional area of type IIX/B muscle fibers. Muscles from FoxP1iSkmTg/Tg mice also showed significant muscle damage and myopathy characterized by the accumulation of p62 and cellular material-filled vesicles, the presence of centrally nucleated myofibers, and were significantly weaker than controls. In the context of cancer cachexia, blocking FoxP1 upregulation prevented the cancer-induced repression of target genes critical to muscle structural integrity and repair, including Myocyte enhancer factor 2c (Mef2c), improved muscle ultrastructure and significantly attenuated muscle fiber atrophy. We further show that the muscle wasting phenotype induced by FoxP1 required the activity of histone deacetylase (HDAC) proteins, which are well-established to cooperate with FoxP1 to mediate gene repression, and which were necessary for FoxP1-dependent repression of Mef2c. In summary, we identify FoxP1 as a negative transcriptional regulator of skeletal muscle mass and function, whose up-regulation mediates cancer-induced muscle wasting. We used microarrays to investigate the genome-wide transcriptional networks regulated by the FoxO1 and FoxP1 transcription factors in skeletal muscle of tumor-bearing mice.
2021-04-28 | GSE153068 | GEO
Project description:Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified an increased production and elevated blood levels of soluble pro-cachectic factor Activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Systemic pharmacological blockade of Activin A using soluble activin receptor type IIB ligand trap prevented muscle wasting in a mouse model of experimental CKD.
2024-03-19 | GSE169316 | GEO
Project description:Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified an increased production and elevated blood levels of soluble pro-cachectic factor Activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single cell sequencing data identified the expression of Activin A in specific kidney cell populations, namely a subpopulation of fibroblasts and cells of the juxtaglomerular apparatus. Based on our findings, we propose that persistent and increased kidney production of pro-cachectic factors combined with a lack of kidney clearance facilitate a vicious signalling kidney-muscle cycle, leading to exacerbated blood accumulation of Activin A, and thereby skeletal muscle wasting in CKD.
2021-04-17 | GSE172252 | GEO
Project description:FoxP1 is sufficient and required for skeletal muscle wasting
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Project description:Systemic muscle wasting drives tumourigenesis
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Project description:Reduced PABPN1 levels cause aging-associated muscle wasting. PABPN1 is a multi-functional regulator of mRNA processing. To elucidate the molecular mechanisms causing PABPN1-mediated muscle wasting, we compared the transcriptome to the proteome in mouse muscles expressing shRNA to PABPN1 (shPab). We found greater variations in the proteome as compared to mRNA expression profiles. Protein accumulation in the shPab proteome was concomitant with reduced proteasomal activity. Notably, protein acetylation appeared to be enriched in shPab versus control proteomes (63%). An acetylome study in shPab muscles revealed prominent peptide deacetylation associated with elevated sirtuin-1 (SIRT1) deacetylase. We show that SIRT1 mRNA levels are controlled by PABPN1 via an alternative polyadenylation site utilization. SIRT1 inhibition reversed PABPN1 activity and muscle cell function. Moreover, deacetylation inhibition increased PABPN1 levels and reversed muscle wasting. We suggest that perturbation of a multifactorial regulatory loop involving PABPN1 and SIRT1 plays an imperative role in aging-associated muscle wasting.
2022-02-28 | PXD011534 | Pride
Project description:Beginning in 2013, sea stars throughout the Eastern North Pacific were decimated by wasting disease, also known as ‘asteroid idiopathic wasting syndrome’ (AIWS) due to its elusive etiology. The geographic extent and taxonomic scale of AIWS meant events leading up to the outbreak were heterogeneous, multifaceted, and oftentimes unobserved; progression from morbidity to death was rapid, leaving few tell-tale symptoms. Here we take a forensic genomic approach to discover candidate genes that may help explain sea star wasting syndrome. We report the first genome and annotation for P. ochraceus, along with differential gene expression (DGE) analyses in four size classes, three tissue types, and in symptomatic and asymptomatic individuals. We integrate nucleotide polymorphisms associated with survivors of the wasting disease outbreak, DGE associated with temperature treatments in P. ochraceus, and DGE associated with wasting in another asteroid Pycnopodia helianthoides. In P. ochraceus, we find DGE across all tissues, among size classes, and between asymptomatic and symptomatic individuals; the strongest wasting-associated DGE signal is in pyloric caecum. We also find previously identified outlier loci co-occur with differentially expressed genes. In cross-species comparisons of symptomatic and asymptomatic individuals, consistent responses distinguish genes associated with invertebrate innate immunity and chemical defense, consistent with context-dependent stress responses, defensive apoptosis, and tissue degradation. Our analyses thus highlight genomic constituents that may link suspected environmental drivers (elevated temperature) with intrinsic differences among individuals (age/size, alleles associated with susceptibility) that elicit organismal responses (e.g. coelomocyte proliferation) and manifest as sea star wasting mass mortality.
2020-02-19 | GSE144422 | GEO