**5. Perspectives**

*Background and Management of Muscular Atrophy*

cells, altering their functions [13, 169].

including diaphragm, limb, and heart muscles, in which death occurs in teenage years to 20s by cardiorespiratory failure [168]. In Duchenne disorder, the affected gene is dystrophin, which has an important structural function in anchoring the muscle fibers to the ECM in the muscular stem cell niche [13]. Moreover, dystrophin, which is expressed by satellite cells, is situated near the cell membrane and coordinates the flow of signaling molecules; therefore, a low level of dystrophin has a direct influence on the downstream cell-intrinsic signaling pathways of satellite

In most of the muscular dystrophies, the structural architecture of muscle cells is fragile, and fibers are doomed to get ruptured during repeated contractions; the stem cell niche is changing in such a way that the skeletal muscles get infiltrated with fat and fibrotic tissue [156, 170, 171]. Muscle ruptures are followed by protein leakage that activates inflammatory cells (lymphocytes, neutrophils, natural killer, macrophages) [172]. In muscular dystrophies, the inflammatory response is distinct than the one in trauma: there are many foci of injury developed in a continuous and asynchronous manner and the inflammatory process becomes chronic, and the ECM becomes thick and rigid, altering the muscular stem cell niche [173, 174]. In the extracellular environment, researchers discovered an accumulation of collagen I, III, IV, V, higher levels of various heparan sulfate proteoglycans and, moreover, a distinct regulation of the expression levels of MMPs and their endogenous inhibitor (TIMPs), together with various serine proteases and their endogenous inhibitors (serpins) [175–182]. Furthermore, the increased levels of matricellular proteins like fibrinogen, dermatopontin, asporin, and periostin were observed, together with a downregulation of fibrillin and nidogen [183–186]. The muscular stem cell niche is also enriched in signaling molecules during this inflammatory process, which influences the myoblast differentiation and fusion [155, 187]. For example, higher levels of prostaglandins, cytokines, and chemokines are described in muscular dystrophy, fact that supports the regenerative failure of dystrophic fibers [188–193]. This long-term inflammatory process changes the satellite cells in such manner that they can no longer compensate for the fiber degeneration, leading to an altered muscle functionality. Diabetes mellitus represents a category of metabolic diseases characterized by a deficiency in insulin generation and function, leading to hyperglycemia, a condition which decreases the antioxidant level and increases the levels of free radical species [194, 195]. Muscle renewal is altered in type 1 and 2 of diabetes mellitus, these patients having a poor lesion-healing capacity [194, 196–198]. There is a fibrotic disposition of collagen and atypical levels of TNFα, TGFβ and ILs in diabetic or obese rats and patients due to the high level of M1 macrophages [199–202]. A sustained exposure to glucose generates an accumulation of glycated lipids and proteins that have an unfavorable impact on myoblasts from both rats and humans [203].

Another dramatic muscular pathology is cachexia. This state occurs as a consequence of various disorders such as AIDS, COPD, cancer, and heart failure and consists in the heavy and accelerated loss of striate muscle mass [204]. Muscular fibers from mice with neoplasms or from cachectic patients present abnormalities in the architecture of the basal lamina and in the membrane of the muscle cells, rather than infiltration of immune cells like in dystrophies or diabetes mellitus [205, 206]. This affected niche together with circulating plasma factors contributes to a hyperactivation of satellite cells and other non-satellite cells including pericytes. Furthermore, satellite cells constantly express Pax-7 self-renewal factor, an action that abolishes the differentiation process, leading to regenerative failure of muscular fibers [1]. Collectively, the data reviewed above showed the importance of stem cell niche behavior in the muscle regenerative process; yet further studies are required to fully understand these complex mechanisms involved in the renewal of normal and

**36**

pathological muscle.

Over the last three decades, researchers found that satellite cells are a heterogenous population of stem cells and dedicated progenitors for myogenesis in striate muscle. With the development of new technologies, like single cell sequencing, mass cytometry, or super resolution imaging, the detailed study of satellite cells during growth, differentiation, and quiescence state is continuously improving [1]. The progress in discovering personalized therapies is slow and full of challenges, especially in the field of rare muscle pathologies, yet the stimulation of endogenous repair as a prospective therapy for muscle diseases should be one of the key perspectives that should be further looked into [207, 208]. The stem cell niche changes in behavior and composition during a lifetime, having tree periods: juvenile, adult, and old age. It is known that there are difficulties in muscular stem cells isolation and preservation due to the fact that they lose their myogenic ability after growing in vitro even for a short period of time [129]. A question that is yet to be answered is whether the use of juvenile stem cells instead of adult ones would provide for more adequate cell cultures, increasing plasticity and improving muscle regenerative therapies. For this purpose, and for a better understanding of skeletal stem cell niche, future challenging studies are needed.
