1. Introduction
Skeletal muscle is one of the most abundant tissues in the human body. It accounts for 40%–45% of the total body massandisnecessaryforgeneratingforcesformovement[1]. Up to a certain threshold, skeletal muscle has the capability of regenerating lost tissue upon injury [2]. Beyond this threshold, the remaining muscle tissue is unable to fully regenerateitsfunction.Thislossofskeletalmusclewithlasting functional impairment is defined as “volumetric muscle loss” (VML)[3–5]. Itcan substantiallyimpactthequalityof life of patients by significantly reducing the functionality of thelocomotionsystem[4]. Frequent reasons for skeletal muscle injuries are highenergy traffic accidents, blast trauma, combat injuries, surgicalandorthopedicsituations(e.g.,aftercompartmentsyndromeortumorresection),orcontusioninjuryduringsports thatleadtoanacutemuscletissueloss[6,7].Approximately 35–55% of sport injuries involve muscle damage at the myofiber level [8]. Those injuries that involve 20% or more
of muscle loss of the respective muscle mass need reconstructivesurgicalprocedures[9].Progressivemusclelosscan resultfrommetabolicdisordersorinheritedgeneticdiseases suchasDuchennemusculardystrophy,AmyotrophicLateral Sclerosis,andpediatricCharcot-Marie-Toothdisease[10–13]. Muscleatrophycanalsobeaconsequenceofperipheralnerve injuries, chronic kidney disease, diabetes, and heart failure [14,15].Upto20%lossofmusclemasscanbecompensated bythehighadaptabilityandregenerativepotentialofskeletal muscle. Beyond this threshold functional impairment is inevitableandcanleadtoseveredisabilityaswellascosmetic deformities, which is why therapeutic options are in urgent demandforthesepatients[4,5,16,17]. Muscleregenerationreliesonaheterogeneouspopulation of satellite cells, interstitial cells, and blood vessels and is mainlycontrolledthroughECMproteinsandsecretedfactors [18, 19]. Normally muscle mass is maintained by a balance between protein synthesis and degradation [20]. In most casesofVML,theregenerationcapabilityofskeletalmuscles isimpeded,becausenecessaryregenerativeelements,mainly
satellite cells, perivascular stem cells, and the basal lamina, arephysicallyremoved[21,22].Throughdenervation,protein degradationpathways(theproteasomalandtheautophagiclysosomal pathways) are activated. Therefore protein degradation rates exceed protein synthesis, which contributes to the muscle atrophy accompanied by gradual decrease of musclewetweightandmusclefiberdiameters[23,24]. Revascularization is typically impaired. The following ischemic conditions favor fibroblast proliferation, fibrosis, and fibrotic scar tissue formation, which leads to further degenerationofthemuscle[25].TheECMcompositionand extent in scar tissues affect many aspects of myogenesis, muscle function, and reinnervation [26]. It can severely constrain motion and thereby aggravate the consequences of muscle tissue loss. Also in chronic muscle loss like Duchenne muscular dystrophy, fibrosis is a major problem [27].Here,theconsistentbreakdownofmyofiberscannotbe fullycompensatedbysatellitecellproliferation.Thefollowing inflammatory processes lead to an altered production of extracellular matrix (ECM) and consequent development of fibrosis and scar tissue formation [27–29]. This scar formationcanbereducedeitherbyinjectionof,forexample, 5-fluorouracil and bleomycin, which antagonizes fibroblast proliferation and neoangiogenesis or by laser therapy with release of contracture and functional improvements after 6–12months’treatment[30,31].Regenerationwithregression of scar tissue and functional recovery can furthermore be optimized with fat grafting [32]. However, reducing scar formation is not enough for promoting muscle tissue repair and regeneration. This reinvigorates clinical and research efforts directed at replacing or regenerating larger volumes ofmuscletissue.