Systemic sclerosis (SSc) is an autoimmune and chronic disease characterized by endothelial dysfunction, immune system dysregulation and fibrosis of skin and internal organs. Gastrointestinal involvement, chronic inflammation, malnutrition, steroid therapy and physical inactivity contribute to the development of sarcopenia among SSc patients. Sarcopenia is quite common in SSc patients with a prevalence of 22.5%, and negatively impacts on morbidity, mortality, rehospitalization rates and healthcare costs. It is known that malnutrition delays digital ulcers (DUs) healing in SSc. Digital ulcers related to SSc are recorded in up-to 50% of patients representing the most important vascular complication that lead to severe reduction the patient's quality of life and relevant disability. Ischemia related to Raynaud phenomenon and impaired angiogenesis are the pathogenic mechanisms of DUs in SSc. In SSc an imbalance between angiogenic and angiostatic factors exists that alters vascular recovery. Impaired angiogenesis is a feature of DUs and several studies showed low serum levels of vascular endothelial growth factor (VEGF) in SSc patients with active DUs. Skeletal muscle is the largest organ in the body and has been identified as a secretor of myokines which participate not only in the regulation of energy homeostasis and nutrient metabolism but also in angiogenesis, as it is the case for VEGF. In skeletal muscle, VEGF plays an essential role not only in angiogenesis, but also in maintenance of the capillary bed. With this project we aim to demonstrate, for the first time, that sarcopenia can be a possible risk factor of DU development in SSc patients. In particular, we speculate that SSc-associated sarcopenia may concur to impaired neoangiogenesis together with the classically recognized factors.
Sarcopenia, i.e. the loss of muscle mass and function is a hallmark of ageing and chronic diseases, which represents a clinical risk factor for the development of disability, increased morbidity and mortality, impaired resilience to external stressors and impaired tolerance to treatments. The pathogenesis of sarcopenia is multifactorial and include insufficient nutrient intake, impaired anabolic response, inflammation-induced increased muscle protein catabolism and low physical activity.
Skeletal muscle is a highly vascularized tissue that can secrete myokines that exert biological functions in muscle itself (autocrine effect) or on short- or long-distant organs (paracrine/endocrine effects) and controls processes such as glucose and lipid metabolism, inflammation and angiogenesis.
Recently, a role for impaired angiogenesis in the pathogenesis of sarcopenia has been proposed, determining a vicious cycle in which sarcopenia may become a causative factor as well as a consequence of altered vessel generation. Patients with sarcopenia have changed production of myokines and it is likely that local and systemic angiogenesis can be altered. Indeed, in elderly people, a diminished density of the capillary network and impaired angiogenesis are present in skeletal muscle, suggesting that the microcirculation might represent an important target for sarcopenia prevention and treatment in ageing and chronic diseases.
Sarcopenia is highly prevalent in SSc patients and it is associated with disease duration, disease severity and skin fibrosis. In scleroderma, disease activity has an effect on muscle mass and strength and both of them are severely impaired during the course of disease. Although sarcopenia in SSc is usually attributed to poor nutritional status and impaired mobility, it cannot be excluded that, also in SSc, a link may exist between sarcopenia and impaired angiogenesis. It is well recognized that in the skeletal muscle, VEGF plays an essential role in angiogenesis. Moreover, quite recently a series of micro-RNAs (miRNAs) have been identified which may promote vascularization. Among these, miRNA-130a is potentially responsible for crosstalk between skeletal muscle and endothelial cells.
In SSc, aberrant miRNA expression is associated to vascular damage and fibrosis in heart, lung and kidney. Down-regulation of miRNA-29 family is common in SSc and correlates with collagen production.
With this project we aim to demonstrate, for the first time, that sarcopenia can be a possible risk factor of DU development in SSc patients. In particular, we speculate that SSc-associated sarcopenia may concur to impaired neoangiogenesis together with the classically recognized factors.
The proposed project is highly innovative and the results obtained could significantly contribute to unravel new pathogenic mechanisms potentially involved in the development of a major complication of SSc, i. e. DUs. However, it cannot be excluded that the present study might provide new insights into the pathogenesis of the systemic vascular changes responsible for multiple organ damage, charactheristic of SSc. It is tempting to hypothesize that the prevention/treatment of sarcopenia with appropriate personalized nutrition and sustainable physical activity programs may become a hallmark of the multimodal treatment for SSc patients, aimed at improving quality of life and prolonging survival.
Essential references
Liakouli V, Mod Rheumatol 2018
Silva I, Clin Rheumatol 2016
Chen JQ, Autoimmune Reviews 2016
Hendrickse P, J Muscle Res Cell Motil 2019