Secreted Protein Acidic and Rich in Cysteine (Sparc) KO Leads to an Accelerated Ageing Phenotype Which Is Improved by Exercise Whereas SPARC Overexpression Mimics Exercise Effects in Mice

Abstract

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein implicated in various functions, including metabolism, tissue regeneration, and functional homeostasis. SPARC/Sparc declines with ageing but increases with exercise. We aim to verify two hypotheses: (1) SPARC deficiency leads to an ageing-like phenotype (metabolic decline, muscle loss, etc.), and (2) SPARC overexpression would mimic exercise, counteract ageing, and improve age-related changes. Our mice experiments are divided into two parts. First, we explore the consequences of Sparc knockout (KO) and compare them to the ageing effects. We also observe the effects of exercise. In the second part, we study the effects of SPARC overexpression and compare them to the exercise benefits. At the end, we make an analysis of the results to point out the analogies between Sparc KO and the ageing-like phenotype on the one hand and make comparisons between SPARC overexpression and exercise in the context of exercise counteracting ageing. The measurements were mainly related to tissue weights, adiposity, metabolism, and muscle strength. The main findings are that Sparc KO reduced glucose tolerance, muscle glucose transporter expression, and abdominal adipose tissue weight but increased glycogen content in the muscle. SPARC overexpression increased muscle strength, muscle mass, and expressions of the muscle glucose transporter and mitochondrial oxidative phosphorylation but lowered the glycemia and the adiposity, especially in males. Collectively, these findings, and the data we have previously reported, show that Sparc KO mice manifest an ageing-like phenotype, whereas SPARC overexpression and exercise generate similar benefits. The benefits are towards counteracting both the SPARC deficiency-induced ageing-like phenotype as well as reversing the age-related changes. The potential applications of these findings are to build/optimize Sparc KO-based animal models of various health conditions and, on the other hand, to develop therapies based on introducing SPARC or targeting SPARC-related pathways to mimic exercise against age-related and metabolic disorders.

Genetic Expression between Ageing and Exercise: Secreted Protein Acidic and Rich in Cysteine as a Potential “Exercise Substitute” Antiageing Therapy

“…In addition, the effects of exercise on skeletal muscle counteract those of ageing [ 23 ]. Not only has SPARC been characterized as an exercise-induced gene, but Sparc KO in mice or SPARC inhibition in the cell culture leads to an ageing-like phenotype [ 24 , 25 ]. Moreover, SPARC overexpression mimics exercise-induced changes [ 24 ].…”

“…Not only has SPARC been characterized as an exercise-induced gene, but Sparc KO in mice or SPARC inhibition in the cell culture leads to an ageing-like phenotype [ 24 , 25 ]. Moreover, SPARC overexpression mimics exercise-induced changes [ 24 ]. Therefore, it seems that a decrease in SPARC expression might contribute to the ageing process, while an increase in SPARC expression could be involved in the exercise-induced changes.…”

“…We previously suggested that the antiageing effect of exercise might be mediated by the exercise-induced increase in SPARC expression, which reverses/counteracts the ageing-associated decline in SPARC/ Sparc expression [ 24 ]. This is supported by a study suggesting that exercise-induced muscle phenotype changes are SPARC-dependent [ 31 ].…”

“…The association between the ageing phenotype and SPARC decline is further supported by the fact that animal models of Sparc KO exhibit ageing-like phenotypes, including accelerated degeneration [ 32 , 33 ], osteopenia [ 34 ], early onset of cataractogenesis [ 35 , 36 ], lack of immune response to lipopolysaccharides [ 37 ], and decreased bone formation [ 38 ]. Furthermore, the involvement of SPARC in exercise-induced antiageing effects is confirmed by SPARC overexpression in mice [ 24 ] or the addition of SPARC to the muscle cell cultures [ 25 ], which also mimics exercise in terms of metabolism and muscle properties. Therefore, SPARC expression levels could be an indicator of whether the phenotype would be for ageing (low SPARC expression) or rather an exercise-induced (antiageing) phenotype (high SPARC expression).…”

Secreted Protein Acidic and Rich in Cysteine as an Exercise-Induced Gene: Towards Novel Molecular Therapies for Immobilization-Related Muscle Atrophy in Elderly Patients

“…This gene was initially characterized as induced by exercise [ 73 , 74 ], potentially mediating exercise-induced muscle phenotype changes [ 75 ] and as up-regulated during skeletal muscle regeneration [ 76 ]. Sparc overexpression mimics exercise, including enhancing muscle mass, strength, metabolism as well as ameliorating glycemia [ 77 ]. SPARC is expressed both in fetal and neonatal muscle and following muscle damage as well [ 78 ].…”