**1. Introduction**

Unlike de novo embryonic muscle formation, adult myogenesis or muscle regeneration in higher vertebrates depends on the extracellular matrix (ECM) scaffold remaining (after tissue damage), serving as a template for the muscle fibres [1]. The mechanisms of embryonic myogenesis are to some extent recapitulated during muscle regeneration (see [2,3] for a more detailed description). In brief, it is during embryonic myogenesis that the first muscle fibres are generated [4]. These are derived from mesoderm structures and are the template fibres for the following wave of additionally generated ones [5,6]. Initially, an exponential proliferation occurs up to a degree where the number of fabricated myonuclei starts decreasing, up until a steady state of synthesis rate is reached [7,8]. This leads to the establishment of a matured muscle, followed by quiescence of the progenitor cells and its occupation within the muscle fibres as satellite cells [9,10]. The myogenic rely on the satellite cells' capacity to become activated, and to proliferate and differentiate (including self-renewal), ensuring an efficient muscle repair [11]. Satellite cells exist in a dormant state (i.e., quiescence or reversible G0 state), retaining the ability to reverse to a proliferative state in response to injury, which is essential for satellite cell pool long-term preservation [12–14]. Both timing and extension of satellite cells' activation and subsequent myoblasts' migration, in response to myotraumas to the injury sites, are partly regulated by a plethora of autocrine and paracrine factors [15,16]. These factors are released either from damaged myofibres, by the ECM or secreted by supporting inflammatory (e.g., neutrophils, macrophages) and interstitial cells, present in the niche or that migrate to the site following injury [17]. Moreover, cell-to-cell interactions are fundamental both during developmental

**Citation:** Mendes, S.; Leal, D.V.; Baker, L.A.; Ferreira, A.; Smith, A.C.; Viana, J.L. The Potential Modulatory Effects of Exercise on Skeletal Muscle Redox Status in Chronic Kidney Disease. *Int. J. Mol. Sci.* **2023**, *24*, 6017. https://doi.org/10.3390/ ijms24076017

Academic Editors: Márcia Carvalho and Luís Belo

Received: 15 February 2023 Revised: 21 March 2023 Accepted: 22 March 2023 Published: 23 March 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

(i.e., embryogenesis) and regenerative myogenesis [i.e., in response to physical activity (PA), trauma or disease]. These interactions allow myoblasts to adhere and fuse with myotubes during myogenesis (initial stage) [18] (Figure 1).

**Figure 1.** Schematic representation of the mammalian skeletal myogenesis process. Upon muscle injury, a resident population of quiescent skeletal muscle satellite cells can become activated, start to proliferate and differentiate into myoblasts. Over the course of several days, these myoblasts fuse together to form multinucleated myotubes. Further, myoblasts can also fuse to the already existing myotubes to create even larger myotubes, which will eventually align to form muscle fibres. This whole process is regulated by many internal and external cues.

Satellite cells sit closely opposed to the myofibres or near capillaries, facilitating their nutrition, sitting within the ECM, which functions as a scaffold to facilitate their purpose [19,20]. Additionally, activated satellite cells undergo symmetric—give rise to two identical daughter-cells that will self-renew satellite stem cell pools—and asymmetric division—generate one stem cell and one daughter-cell committed to progress through the myogenic lineage and eventually will join the myofibre, ensuring repetitive rounds of regeneration [21,22]. These myofibres are formed by myoblast fusion, producing multinucleated myotubes, further maturing into myofibres (see [23,24] for details). Each myofibre is surrounded by a specialised basal lamina (BL)—endomysium—that harbours a specialised plasma membrane—sarcolemma—allowing neuronal signal transduction and structural stability [25,26]. The sarcolemma is anchor to the BL through transmembrane proteins—dystrophin-associated glycoprotein complex (DGC)—which allow the connection of cytoskeleton to ECM [27].

Muscle fibres are the base of skeletal muscle, being their basic contractile units [28]. These fibres are surrounded by a layer of connective tissue and are grouped in bundles [25,26]. Each myofibre is connected to a single motor neuron and expresses characteristics (e.g., molecules and metabolic enzymes) for contractile function, specifying the myofibre contractile properties, ranging from slow-contracting, fatigue-resistant/oxidative (type I) to fast-contracting, non-fatigue-resistant/glycolytic (type II) fibres. Moreover, the proportion of each fibre type determines overall contractile property within the muscle [29]. The connective tissue that surrounds the skeletal muscle functions as a framework, combining myofibres with myotendinous junctions (i.e., the place where myofibres attach to the skeleton), transforming myofibre contraction into movement [30]. Hence, the skeletal muscle functional properties are dependent on myofibres, motor neurons, blood vessels and ECM.

Skeletal muscle maintenance is accomplished by an interplay between multiple signalling pathways, including two major ones that control protein synthesis, IGF1-PI3K-Akt-mTOR pathway (positive regulator) and myostatin-Smad2/3 pathway (negative regulator) [3,31]. These interconnected pathways control and coordinate hypertrophic and atrophic signalling, creating a balance between protein synthesis and proteolysis [32,33].

Skeletal muscle cells are not isolated elements; they are inserted in their ecological niche, creating a social network with their surroundings. This context consists of interstitial cells, vascular features, ECM proteins and soluble factors, which together constitute the skeletal muscle microenvironment [34]. This microenvironment must be adequate to support skeletal muscle functions and allow a suitable regeneration after assault, such as that imposed by disease (discussed in Sections 3, 4 and 6) or exercise (discussed in Sections 4–6). When this does not occur, we may be confronted with processes leading to muscle wasting.
