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Brown Fat Promotes Muscle Growth During Regeneration.

ABSTRACT: Accumulation of adipose tissue around and within muscles is highly correlated with reduced strength, functional limitations, and poor rehabilitative outcomes. Given the intimate physical contact between these tissues, paracrine cross-talk is a likely mediator of this association. The recent discovery that muscle-associated adipose tissue exhibits features of beige fat has suggested that this cross-talk may be modifiable, as beige fat can be stimulated to assume features of brown fat. In this work, we describe a novel intermuscular fat transplant model in the mouse rotator cuff to investigate cross-talk between muscle and adipose tissue. Specifically, we examine the role of transplanted fat phenotype on muscle regeneration by transplanting pieces of classical brown (interscapular), beige (inguinal), or white (epididymal) adipose tissue in conjunction with cardiotoxin injection to the adjacent supraspinatus muscle. Transplantation of brown fat, but not beige or white, significantly increased muscle mass, fiber cross-sectional area and contractile force production compared with sham injury. This effect was not seen when cardiotoxin was delivered to a distant muscle, or when adjacent muscles were injected with saline indicating that the effect is localized and specifically targeting the regenerative process. Thus, we conclude that local signaling between fat and muscle varies by phenotype and that brown fat supports regeneration. Clinical significance: Our findings suggest that the phenotype of muscle-associated fat could be a novel therapeutic target to modulate fat-muscle signaling. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1817-1826, 2019.

SUBMITTER: Bryniarski AR

PROVIDER: S-EPMC6824921 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Project description:BackgroundTissue regeneration requires a series of steps, beginning with generation of the necessary cell mass, followed by cell migration into damaged area, and ending with differentiation and integration with surrounding tissues. Temporal regulation of these steps lies at the heart of the regenerative process, yet its basis is not well understood. The ability of zebrafish to dedifferentiate mature "post-mitotic" myocytes into proliferating myoblasts that in turn regenerate lost muscle tissue provides an opportunity to probe the molecular mechanisms of regeneration.ResultsFollowing subtotal excision of adult zebrafish lateral rectus muscle, dedifferentiating residual myocytes were collected at two time points prior to cell cycle reentry and compared to uninjured muscles using RNA-seq. Functional annotation (GAGE or K-means clustering followed by GO enrichment) revealed a coordinated response encompassing epigenetic regulation of transcription, RNA processing, and DNA replication and repair, along with protein degradation and translation that would rewire the cellular proteome and metabolome. Selected candidate genes were phenotypically validated in vivo by morpholino knockdown. Rapidly induced gene products, such as the Polycomb group factors Ezh2 and Suz12a, were necessary for both efficient dedifferentiation (i.e. cell reprogramming leading to cell cycle reentry) and complete anatomic regeneration. In contrast, the late activated gene fibronectin was important for efficient anatomic muscle regeneration but not for the early step of myocyte cell cycle reentry.ConclusionsReprogramming of a "post-mitotic" myocyte into a dedifferentiated myoblast requires a complex coordinated effort that reshapes the cellular proteome and rewires metabolic pathways mediated by heritable yet nuanced epigenetic alterations and molecular switches, including transcription factors and non-coding RNAs. Our studies show that temporal regulation of gene expression is programmatically linked to distinct steps in the regeneration process, with immediate early expression driving dedifferentiation and reprogramming, and later expression facilitating anatomical regeneration.

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Brown Fat Promotes Muscle Growth During Regeneration.

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