Relative Contributions of Myostatin and the GH/IGF-1 Axis in Body Composition and Muscle Strength

Abstract

Myostatin, a negative regulator of muscle growth, is considered a potential therapeutic agent for individuals suffering from various muscle wasting and strength declining diseases because inhibiting Mstn signaling leads to muscular hypertrophy. In this study we investigate the interaction between myostatin and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in muscle function and strength. To this end, we measured hind limb grip strength and myostatin levels in two mouse models of GH gene manipulation; GH receptor knockout (GHR-/-) mice which have reduced GH/IGF-1 action, and bovine GH transgenic (bGH) mice which have excess GH/IGF-1 action. We found that specific muscle force was significantly reduced in bGH mice, and significantly increased in GHR-/- mice, compared to their respective littermate wild type controls. The expression of the mature form of myostatin was significantly increased in bGH mice, and unchanged in GHR-/- mice. In the bGH mice, the high levels of mature myostatin were accompanied by increase body weight and lean mass, consistent with other published results indicating that the IGF-1 signaling pathway is dominant over that of Mstn. Our results also suggest that in these mouse models there is an inverse relationship between muscle strength and levels of myostatin and GH, since constitutive overexpression of GH resulted in elevated levels of mature myostatin in muscle, accompanied by a reduction in strength. By contrast, in the GHR-/- mice with reduced levels of IGF-1, mature myostatin levels were unchanged and muscle strength was increased.

Relationship Between Sarcopenia and Cardiovascular Diseases in the Elderly: An Overview

“…GH is involved in the regulation of skeletal muscle growth mainly through insulin growth factors. It can increase skeletal muscle mass but has no noticeable effect on muscle strength ( 116 ). Notably, GH can increase the risk of fluid retention and insulin resistance and adversely affect the cardiovascular system.…”

Experimental Models of Sarcopenia: Bridging Molecular Mechanism and Therapeutic Strategy

“…The depletion of 4E-BPs is associated with perturbed energy metabolism in skeletal muscles, and it has also been suggested that 4E-BP can be a target of sarcopenia intervention [158]. The use of growth hormone receptor knockout (GHR −/− ) and bovine GH mice provided evidence that the insulin-like growth factor 1 (IGF-1) signaling pathway predominantly regulates myostatin, which is a negative regulator of myogenesis [159]. The correlation between mitochondria and muscle atrophy has been elucidated using Opa1 −/− mice.…”

Increased longevity due to sexual activity in mole-rats is associated with transcriptional changes in the HPA stress axis

“…This gene was found to be expressed most strongly in ovary and liver and was strongly up-regulated in the breeders´ ovaries and adrenal glands (Table 1). IGF1 codes for a well-known key regulator of anabolic effects such as cell proliferation, myogenesis, and protein synthesis (Schiaffino and Mammucari 2011;Jung and Suh 2014) and has a tight functional relation to GH (gene: GH1) another key anabolic regulator upstream of IGF1; together, these factors form the so-called GH/IGF1 axis (Cannata et al 2010;Junnila et al 2013;Bodart et al 2015;Raisingani et al 2017;Carotti et al 2018;Lozier et al 2018). Also, GH1 was strongly up-regulated in breeders in its known principal place of synthesis, the pituitary gland (Table 1).…”