Platelet-based applications such as platelet-rich plasma (PRP) and platelet releasate have gained unprecedented attention in regenerative medicine across a variety of tissues as of late. The rationale behind utilizing PRP originates in the delivery of key cytokines and growth factors from α-granules to the targeted area, which in turn act as cell cycle regulators and promote the healing process across a variety of tissues. The aim of the present review is to assimilate current experimental evidence on the role of platelets as biomaterials in tissue regeneration, particularly in skeletal muscle, by integrating findings from human, animal and cell studies. This review is composed of 3 parts: firstly, we review key aspects of platelet biology that precede the preparation and use of platelet-related applications for tissue regeneration. Secondly, we critically discuss relevant evidence on platelet-mediated regeneration in skeletal muscle focusing on findings from (i) clinical trials, (ii) experimental animal studies and (iii) cell culture studies; and thirdly, we discuss the application of platelets in the regeneration of several other tissues including tendon, bone, liver, vessels and nerve. Finally, we review key technical variations in platelet preparation that may account for the large discrepancy in outcomes from different studies. This review provides an up-to-date reference tool for biomedical and clinical scientists involved in platelet-mediated tissue regenerative applications.

Aim:The use of platelets as biomaterials has gained intense research interest.However, the mechanisms regarding platelet-mediated skeletal myogenesis remain to be established. The aim of this study was to determine the role of platelet releasate in skeletal myogenesis and muscle stem cell fate in vitro and ex vivo respectively. Methods: We analysed the effect of platelet releasate on proliferation and differentiation of C2C12 myoblasts by means of cell proliferation assays, immunohistochemistry, gene expression and cell bioenergetics. We expanded in vitro findings on single muscle fibres by determining the effect of platelet releasate on murine skeletal muscle stem cells using protein expression profiles for key myogenic regulatory factors. Results: TRAP6 and collagen used for releasate preparation had a more pronounced effect on myoblast proliferation vs thrombin and sonicated platelets (P < 0.05). In addition, platelet concentration positively correlated with myoblast proliferation. Platelet releasate increased myoblast and muscle stem cell proliferation in a dose-dependent manner, which was mitigated by VEGFR and PDGFR inhibition. Inhibition of VEGFR and PDGFR ablated MyoD expression on proliferating muscle stem cells, compromising their commitment to differentiation in muscle fibres (P < 0.001). Platelet releasate was detrimental to myoblast fusion and affected differentiation of myoblasts in a temporal manner. Most importantly, we show that platelet releasate promotes skeletal myogenesis through the PDGF/ VEGF-Cyclin D1-MyoD-Scrib-Myogenin axis and accelerates skeletal muscle regeneration after acute injury. Conclusion: This study provides novel mechanistic insights on the role of platelet releasate in skeletal myogenesis and set the physiological basis for exploiting platelets as biomaterials in regenerative medicine. K E Y W O R D Sgrowth factors, platelet releasate, platelet-rich plasma, regeneration, satellite cells, skeletal muscle

Aim The prevalence of obesity is a major risk factor for cardiovascular and metabolic diseases including impaired skeletal muscle regeneration. Since skeletal muscle regenerative capacity is regulated by satellite cells, we aimed to investigate whether a high‐fat diet impairs satellite cell function and whether this is linked to fatty acid uptake via CD36. We also aimed to determine whether loss of CD36 impacts on muscle redox homeostasis and skeletal muscle regenerative capacity. Methods We studied the impact of a high‐fat diet and CD36 deficiency on murine skeletal muscle morphology, redox homeostasis, satellite cell function, bioenergetics and lipid accumulation in the liver. We also determined the effect of CD36 deficiency on skeletal muscle regeneration. Results High‐fat diet increased body weight, intramuscular lipid accumulation and oxidative stress in wild‐type mice that were significantly mitigated in CD36‐deficient mice. High‐fat diet and CD36 deficiency independently attenuated satellite cell function on single fibres and myogenic capacity on primary satellite cells. CD36 deficiency resulted in delayed skeletal muscle regeneration following acute injury with cardiotoxin. CD36‐deficient and wild‐type primary satellite cells had distinct bioenergetic profiles in response to palmitate. High‐fat diet induced hepatic steatosis in both genotypes that was more pronounced in the CD36‐deficient mice. Conclusion This study demonstrates that CD36 deficiency protects against diet‐induced obesity, intramuscular lipid deposition and oxidative stress but results in impaired muscle satellite cell function, delayed muscle regeneration and hepatic steatosis. CD36 is a key mediator of fatty acid uptake in skeletal muscle, linking obesity with satellite cell function and muscle regeneration.