Teng and Huang Stem Cell Research & Therapy (2019) 10:103 https://doi.org/10.1186/s13287-019-1186-0 REVIEW Open Access The effect of type 2 diabetes mellitus and obesity on muscle progenitor cell function Shuzhi Teng* and Ping Huang* Abstract In addition to its primary function to provide movement and maintain posture, the skeletal muscle plays important roles in energy and glucose metabolism. In healthy humans, skeletal muscle is the major site for postprandial glucose uptake and impairment of this process contributes to the pathogenesis of type 2 diabetes mellitus (T2DM). A key component to the maintenance of skeletal muscle integrity and plasticity is the presence of muscle progenitor cells, including satellite cells, fibroadipogenic progenitors, and some interstitial progenitor cells associated with vessels (myo-endothelial cells, pericytes, and mesoangioblasts). In this review, we aim to discuss the emerging concepts related to these progenitor cells, focusing on the identification and characterization of distinct progenitor cell populations, and the impact of obesity and T2DM on these cells. The recent advances in stem cell therapies by targeting diabetic and obese muscle are also discussed. Keywords: Satellite cell, muscle progenitor cell, T2DM, Obesity Background A major metabolic defect associated with T2DM is the The incidence of overweight has been increasing dramatic- failure of proper glucose utilization by peripheral tissues ally worldwide due to increased uptake of high-calorie food, such as skeletal muscle and adipose tissue, the primary lack of physical activity, and genetic predisposition. Accord- targets of insulin-stimulated glucose uptake. In healthy ingly, obesity and its associated metabolic diseases such as humans, 70–80% of glucose uptake occurs in skeletal type 2 diabetes mellitus (T2DM) have become an epidemic muscle in the postprandial state through both health threat and economic burden [1]. According to a re- insulin-dependent phosphoinositide-3-kinase-protein kin- cent study, by 2025, global obesity prevalence is expected ase B (PI3K-PKB/AKT) pathway and insulin-independent to reach 18% in men and surpass 21% in women [2]. From glucose-stimulated Baf60c-Deptor-AKT pathway [5, 6]. 1980 to 2014, global age-standardized diabetes prevalence Moreover, studies of genetically predisposed individuals increased from 4.3 to 9.0% in men and from 5.0 to 7.9% in indicate that insulin resistance in muscle is the primary or women [3]. Both genetic and environmental factors play initiating defect leading to the ultimate development of pivotal roles in the pathogenesis of T2DM, among them T2DM [7, 8]. Skeletal muscle not only plays an important obesity is a major risk factor—around 50% of obese subjects role in the pathogenesis of T2DM but also undergoes sig- will develop T2DM at some stage [4]. While insulin resist- nificant structural, metabolic, and functional changes ance in peripheral tissues is often an early sign of develop- under obese and diabetic conditions, such as muscle atro- ing diabetes, pancreatic β cell function is damaged phy [9, 10], fiber-type transition [11], impaired glucose up- gradually during disease progression. Over time chronic take [12], glycogen synthesis [13, 14], fatty acid oxidation hyperglycemia and hyperlipidemia impair cellular functions, [15], and altered myokine secretion [16, 17], which ultim- which eventually lead to various complications including ately lead to muscle weakness and poor exercise diabetic retinopathy, nephropathy, neuropathy, diabetic performance. foot, and cardiovascular diseases [4]. Many of the morphological features of muscle atrophy resemble those seen in sarcopenia, an age-associated loss * Correspondence: [email protected]; [email protected] of skeletal muscle mass and function [18]. Both muscle Shuzhi Teng and Ping Huang are co-corresponding authors. The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune atrophy and sarcopenia are characterized by a decrease College of Medicine, Jilin University, 126 Xinmin Street, Changchun, Jilin in myofiber size and muscle mass, and the ensuing loss 130021, People’s Republic of China © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Teng and Huang Stem Cell Research & Therapy (2019) 10:103 Page 2 of 15 of muscle strength. Loss of appendicular lean mass and serves as a major contributor to the postnatal muscle reduced skeletal muscle strength are commonly ob- growth and repair after injury or disease [38, 39]. In adult- served in T2DM patients despite gender and ethnicity hood, satellite cells remain quiescent under normal condi- and the incidence increases with aging [19, 20]. It is esti- tions. Upon injury or in diseased states, satellite cells are mated that sarcopenia is present in about 5 to 10 % of reactivated, proliferating to generate a pool of myoblasts, persons over 65 years of age [21], whereas the T2DM which then differentiate and fuse with damaged fibers or patients have two to three times higher prevalence of fuse with each other to generate entirely new myofibers. sarcopenia than non-diabetic individuals [22, 23] due to Meanwhile, some myoblasts remain undifferentiated and glucose toxicity, insulin resistance, and oxidative stress return to the quiescent state to replenish the satellite cell [21]. In addition, intermuscular adipose tissue infiltration pool. During muscle development and regeneration, myo- is increased in persons with obesity, diabetes, and per- genic regulatory factors (MRFs) Myf5, MyoD, MRF4, and ipheral neuropathy [24]. This ectopic fat accumulation is myogenin are activated for entry of satellite cells into the associated with impaired muscle function and forms the myogenic program [40]. The importance of satellite cells basis of obese sarcopenia [24]. for muscle regeneration is reinforced by genetic ablation A key component to the maintenance of skeletal of Pax7 expressing cells after acute injury. Lepper and muscle integrity and plasticity is the presence of muscle colleagues found that such elimination completely blocked progenitor cells, including satellite cells, fibroadipogenic muscle regeneration, thus verified that satellite cells, as progenitors, myo-endothelial cells, and other interstitial adult stem cells, are indispensable for acute injury-in- progenitor cells [25–29]. These heterogenous groups of duced muscle regeneration [39]. cells are endowed with multilineage developmental po- tential and may contribute to the pathogenesis as well as the treatment of muscle diseases. The proliferation and differentiation of satellite cells are Accumulating evidence indicates that diabetic and attenuated in diabetic muscles obese conditions not only cause dramatic structural, The impairment of muscle regeneration was observed in metabolic and functional changes of skeletal muscle fi- animal studies under hyperglycemia and/or lipotoxicity bers but also display detrimental effects on these pro- conditions, but the detailed changes especially alter- genitor cells [30, 31]. Therefore, fully characterization of ations of satellite cells vary from study to study, and distinct progenitor cell populations and understanding some results are even conflicting (Table 1). Using a the impact of aging, obesity, and T2DM on these cells mouse model of insulin resistance achieved by high-fat will aid to extend our understanding of these health con- diet (HFD) feeding for 8 months, Hu et al. observed ditions and shed light on developing novel therapeutic smaller regenerating myofibers plus more collagen de- interventions. position after cardiotoxin injury [30]. However, satellite cell activation or proliferation was intact as assessed by Effect of T2DM and obesity on skeletal muscle bromodeoxyuridine (BrdU; an analog of the nucleoside stem cell—satellite cell thymidine) incorporation and by the expression of myo- Satellite cell discovery and function genic transcription factors. Instead, the deficits in muscle The satellite cell was first identified by transmission regeneration were principally related to increased ex- electron microscopy on frog muscle and named after its pression of phosphatase and tensin homolog (PTEN), anatomical localization: mononuclear cell wedged be- which reduced phosphatidylinositol (3,4,5)-trisphosphate tween basal lamina and the plasma membrane of myofi- (PIP3) in muscle, inhibited AKT signaling, and impaired ber, like a “satellite” cell “orbiting” the muscle fiber when myofiber maturation [30]. viewed in cross-section [25]. Shortly afterwards, the sat- On the other hand, HFD-feeding 3-week-old mice for ellite cell was found in other vertebrates including hu- just 3 weeks resulted in overweight, decreased satellite cell man [32]. Subsequent studies proved that satellite cells content and muscle mass, and reduced regenerative cap- are capable of proliferation and myogenic differentiation ability [41]. In another study, HFD-feeding 4-week-old in vitro and in vivo [33, 34]. Recent studies further