Platelet releasate normalises the compromised muscle regeneration in a mouse model of hyperlipidaemia

Abstract

New Findings What is the central question of this study?What is the impact of obesity‐independent hyperlipidaemia on skeletal muscle stem cell function of ApoE‐deficient (ApoE–/–) mice? What is the main finding and its importance?Compromised muscle stem cell function accounts for the impaired muscle regeneration in hyperlipidaemic ApoE–/– mice. Importantly, impaired muscle regeneration is normalised by administration of platelet releasate. Abstract Muscle satellite cells are important stem cells for skeletal muscle regeneration and repair after injury. ApoE‐deficient mice, an established mouse model of hyperlipidaemia and atherosclerosis, show evidence of oxidative stress‐induced lesions and fat infiltration in skeletal muscle followed by impaired repair after injury. However, the mechanisms underpinning attenuated muscle regeneration remain to be fully defined. Key to addressing the latter is to understand the properties of muscle stem cells from ApoE‐deficient mice and their myogenic potential. Muscle stem cells from ApoE‐deficient mice were cultured both ex vivo (on single fibres) and in vitro (primary myoblasts) and their myogenic capacity was determined. Skeletal muscle regeneration was studied on days 5 and 10 after cardiotoxin injury. ApoE‐deficient muscle stem cells showed delayed activation and differentiation on single muscle fibres ex vivo. Impaired proliferation and differentiation profiles were also evident on isolated primary muscle stem cells in culture. ApoE‐deficient mice displayed impaired skeletal muscle regeneration after acute injury in vivo. Administration of platelet releasate in ApoE‐deficient mice reversed the deficits of muscle regeneration after acute injury to wild‐type levels. These findings indicate that muscle stem cell myogenic potential is perturbed in skeletal muscle of a mouse model of hyperlipidaemia. We propose that platelet releasate could be a therapeutic intervention for conditions with associated myopathy such as peripheral arterial disease.

Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles

“…Interestingly, several studies have explored the therapeutic use of the platelet-rich plasma (PRP), i.e., the component of the blood devoid of white and red blood cells but rich in platelets and platelet-secreted factors (releasate). In particular, injection of the PRP has been proposed to boost wound healing and regeneration in a number of tissues [50][51][52][53][54][55][56][57][58] , including skeletal muscle [59][60][61][62][63][64] . However, it remains largely undetermined whether platelets are necessary for skeletal muscle regeneration beyond their role in hemostasis, and whether platelet-secreted factors are required for any step of muscle repair.…”

Transgene-free direct conversion of murine fibroblasts into functional muscle stem cells

“…2g, h ). Surprisingly, the remaining Pax7 + cell population (Pax7_PGs-3) demonstrated expression of genes indicative of satellite cells in vivo, including Apold1 53 , Apoe 53 , 54 , CD9 55 , Cebpb 56 and most notably absence of Cdkn1c , a myoblast marker reportedly undetectable in muscle stem cells 57 (Figs. 2g–i and S6a–c ).…”

Signaling roles of platelets in skeletal muscle regeneration

“…[29][30][31]33] In agreement with this possibility, an interesting study found that intraperitoneal injection of the PR from wild-type platelets can rescue the muscle regeneration deficits of ApoE knockout mice, at least in part by promoting myoD and myogenin expression in differentiating myoblasts, and by promoting the growth of newly formed myofibers. [35] The decreased regenerative capacity of ApoE knockout mice arises from hyperlipidemia and metabolic stress, suggesting that the systemic delivery of the PR from wild-type mice may help normalize metabolism in ApoE knockout mice, possibly via ApoE released by platelets. [2,3] Further studies should determine whether platelets and the PR influence myogenesis in distinct disease contexts and whether this response also occurs in vivo in physiological conditions (i.e., in wild-type mice).…”