Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health

Front Endocrinol (Lausanne). 2024 May 14:15:1404047. doi: 10.3389/fendo.2024.1404047. eCollection 2024.

Abstract

Introduction: Growth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions, including muscle wasting and sarcopenia. However, the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated. Moreover, the role of GDF15 intracellular precursor, pro-GDF15, in human skeletal muscle (SM-GDF15) is not totally understood. In order to clarify these points, the association of both forms of GDF15 with parameters of muscle strength, body composition, metabolism and inflammation was investigated.

Methods: the levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies, respectively, of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI), either young (<40 years-old) or old (>70 years-old). Other parameters included in the analysis were Isometric Quadriceps Strength (IQS), BMI, lean and fat mass percentage, Vastus lateralis thickness, as well as circulating levels of Adiponectin, Leptin, Resistin, IGF-1, Insulin, IL6, IL15 and c-PLIN2. Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed.

Results: c-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI, while only in LLMI associated with increased levels of Resistin. Moreover, in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels, but interestingly SM-GDF15 is lower in LLMI with respect to HS. Furthermore, a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA. In particular HS, LLMI over 70 years or under 40 years of age were discriminated based on SM-GDF15, c-GDF15 and Insulin levels, respectively.

Conclusion: our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state.

Keywords: GDF15; aging; biomarkers; inflammaging; muscle health.

MeSH terms

  • Adult
  • Aged
  • Biomarkers* / blood
  • Body Composition
  • Female
  • Growth Differentiation Factor 15* / blood
  • Growth Differentiation Factor 15* / metabolism
  • Humans
  • Male
  • Middle Aged
  • Muscle Strength*
  • Muscle, Skeletal* / metabolism
  • Sarcopenia / blood
  • Sarcopenia / metabolism

Substances

  • Growth Differentiation Factor 15
  • GDF15 protein, human
  • Biomarkers

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The work has been co-funded from Next Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8 – Project Age-It: “Ageing Well in an Ageing Society” to SS. This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022]. The work was also co-funded from the Italian Ministry of University and Research (MUR) PRIN 2022, Project # 2022KS8T4N “GDF15 as a key player and a potential target to tackle ageing and age-associated diseases: an in silico, in vitro and ex vivo study” to SS.