The impact on high-fat diet on skeletal muscle stem cell recruitment in CD36 deficient mice

The prevalence of obesity is a major risk factor for cardiovascular and metabolic diseases including impaired skeletal muscle regeneration. Given the importance of skeletal muscle function in the context of obesity, it is paramount to understand the underlying mechanisms of impaired muscle health. Since skeletal muscle regeneration is regulated by muscle stem cells, the so-called satellite cells (SC), this thesis aims to investigate the effects of diet-induced obesity (DIO) on SC function. This study provides evidence that SC function is impaired in obesity, possibly linked to ectopic lipid infiltration via the fatty acid translocase CD36. Ectopic lipid infiltration was further linked to altered gene expression involved in skeletal muscle redox homeostasis and lipid metabolism. The CD36-deficient mouse model (CD36 KO) used for this study provides, for the first time, evidence of improved redox signalling and decreased oxidative stress in skeletal muscle under high-fat diet conditions, potentially linked to an altered mitochondrial bioenergetic profile. CD36 KO mice showed improved skeletal muscle lipid metabolism but interestingly developed signs of hepatic steatosis when exposed to a high-fat diet. Furthermore, the observed impairment of SC function in WT animals on a high-fat diet was attenuated in CD36 deficiency. However, CD36 was also identified as a key regulator of SC terminal differentiation. CD36 KO mice showed impaired regeneration after acute skeletal muscle injury, possibly linked to the decreased SC differentiation capacity. Additionally, this study reports a decrease in macrophage infiltration in CD36 KO mice following skeletal muscle injury, possibly due to inefficient inflammation resolution, subsequently resulting in impaired regeneration.This demonstrates that CD36 deficiency protects against DIO, intramuscular lipid deposition and oxidative stress but results in impaired SC differentiation, delayed muscle regeneration and hepatic steatosis. CD36 is a key mediator of fatty acid uptake in skeletal muscle, linking obesity with SC function and muscle regeneration

Loss of CD36 protects against diet-induced obesity but results in impaired muscle stem cell function, delayed muscle regeneration and hepatic steatosis

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 dietinduced 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

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

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 lessions 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

Novel insights into the use of platelet releasate as a therapeutic approach for tissue regeneration

Annual Conference of the British-Cardiovascular-Society (BCS) - Digital Health Revolution (2019. Manchester, England