The origin of intermuscular adipose tissue and its pathophysiological implications

Abstract

The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66(shc), mitochondrial ROS production, PKCβ) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia.

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

“…56 Those cells proliferate and differentiate in response to muscle damage, and their existence may explain the sarcopenia observed in elderly and obese individuals. 57 Perhaps the altered lineage choice observed in the cardiac MSCs isolated from aged animals results from a similar mechanism, a common fibroblast or adipocyte progenitor that preferentially gives rise to adipocytes in older age and exhibits compromised maturation toward the myofibroblast phenotype. Because AICAR reduces adipogenesis in preadipocytes, 19,37 it was assumed that by applying AICAR together with adipocytic differentiation medium we would reduce the formation of adipocytes in the aged stem cell culture.…”

Inhibition of adipogenic differentiation by myostatin is alleviated by arginine supplementation in porcine-muscle-derived mesenchymal stem cells

“…Satellite cells or MSCs residing in postnatal muscle can be induced to differentiate into adipocytes [4][5][6][7], and are believed to be the origin of IMF. The differentiation of MSCs in skeletal muscle into adipocytes leads to increased adipocyte number and lipid accumulation [8], and investigation into the modulation of adipogenic differentiation of muscle-derived MSCs would therefore improve our understanding of the mechanisms of IMF deposition, and allow the exploration of novel approaches to improving the IMF content.…”

“…The IMF content thus depends on the adipocyte number and lipid accumulation. Satellite cells or mesenchymal stem cells residing in postnatal muscle have been shown to differentiate into adipocytes [4][5][6][7], and are believed to be the source of IMF [8].…”

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

“…Besides the excessive visceral deposition, several pathogenetic mechanisms are implicated, including brown to white fat transdifferentiation, mitochondrial damage and decreased mitochondrial biogenesis, an increased adipose cell size, a decreased insulin sensitivity of fat cells, and the failure of their storage function with the consequent peripheral lipotoxicity (Virtue & Vidal-Puig 2010), macrophage infiltration, and inflammation along with qualitative and/or quantitative changes in adipokine production (Vettor et al 2005), alteration in the angiogenetic process, and fibrosis development. Recently, stem cell abnormalities have also been described with alteration of the adipogenic process within adipose tissue or as an abnormal adipogenetic differentiation of stem cells residing in other organs (Aguiari et al 2008, Vettor et al 2009). The resulting metabolic consequences include abdominal obesity, insulin resistance, and atherogenic dyslipidemia along with a pro-thrombotic, inflammatory profile that defines the MetS.…”