Irisin ameliorates age‐associated sarcopenia and metabolic dysfunction

Abstract

Background Age-associated sarcopenia is characterized of progressed loss of skeletal muscle power, mass, and function, which affects human physical activity and life quality. Besides, accompanied with sarcopenia, aged population also faces a series of metabolic dysfunctions. Irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), is a myokine induced by exercise and has been shown to exert multiple beneficial effects on health. The goal of the study is to investigate the alterations of Fndc5/irisin in skeletal muscles during ageing and whether irisin administration could ameliorate age-associated sarcopenia and metabolic dysfunction. Methods The mRNA and protein levels of FNDC5/irisin in skeletal muscle and serum from 2-and 24-month-old mice or human subjects were analysed using qRT-PCR and western blot. FNDC5/irisin knockout mice were generated to investigate the consequences of FNDC5/irisin deletion on skeletal muscle mass, as well as morphological and molecular changes in muscle during ageing via histological and molecular analysis. To identify the therapeutic effects of chronic irisin treatment in mice during ageing, in vivo intraperitoneal administration of 2 mg/kg recombinant irisin was performed three times per week in ageing mice (14-month-old) for 4 months or in aged mice (22-month-old) for 1 month to systematically investigate irisin's effects on age-associated sarcopenia and metabolic performances, including grip strength, body weights, body composition, insulin sensitivity, energy expenditure, serum parameters and phenotypical and molecular changes in fat and liver. Results We showed that the expression levels of irisin, as well as its precursor Fndc5, were reduced at mRNA and protein expression levels in muscle during ageing. In addition, via phenotypic analysis of FNDC5/irisin knockout mice, we found that FNDC5/irisin deficiency in aged mice exhibited aggravated muscle atrophy including smaller grip strength (À3.23%, P < 0.05), muscle weights (quadriceps femoris [QU]: À20.05%; gastrocnemius [GAS]: À17.91%; tibialis anterior [TA]: À19.51%, all P < 0.05), fibre size (QU: P < 0.01) and worse molecular phenotypes compared with wild-type mice. We then delivered recombinant irisin protein intraperitoneally into ageing or aged mice and found that it could improve sarcopenia with grip strength (+18.42%, P < 0.01 or +13.88%, P < 0.01), muscle weights (QU: +9.02%, P < 0.01 or +16.39%, P < 0.05), fibre size (QU: both P < 0.05) and molecular phenotypes and alleviated age-associated fat tissues expansion, insulin resistance and hepatic steatosis (all P < 0.05), accompanied with altered gene signatures. Conclusions Together, this study revealed the importance of irisin in the maintenance of muscle physiology and systematic energy homeostasis during ageing and suggested a potent therapeutic strategy against age-associated metabolic diseases via irisin administration.

Biomarkers of aging

“…For example, FGF21 has been proposed to be an aging intervention hormone, which induces browning of white fat, while FGF6 is shown to act as a proliferative factor for ASPC hyperplasia and prevents fibrosis and maintain AT homeostasis during aging (Liu et al, 2023a). Meanwhile, exercise-induced myokine Irisin promotes browning and improves age-associated metabolic dysfunction while its level declines under sarcopenia (Boström et al, 2012;Guo et al, 2023). On the other hand, cold exposure leads to increased hepatic acylcarnitine production and thermogenesis, which is impaired in aged mice (Simcox et al, 2017).…”

Chronic Critical Illness-Induced Muscle Atrophy: Insights From a Trauma Mouse Model and Potential Mechanism Mediated via Serum Amyloid A

“…The overall grip strength was evaluated using the Grip Strength Meter (Chatillon DFX II; Ametek) in tension model as previously reported (33,34). The maximum force (gF) exerted by the mouse while grasping specially designed pull bar assemblies was recorded.…”

Deciphering the Role of the MST1/2-YAP Axis in Irisin-Treated Aplastic Anemia: Implications for Mesenchymal Stem Cell Function

“…However, the mechanism of action of Irisin and its speci c functions in AA remain unclear. To tackle this issue, researchers have commenced investigating Irisin on a molecular level to discover novel treatments for AA [21].…”