Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?

Abstract

Myostatin, also known as growth differentiation factor 8 (GDF8), is a transforming growth factor-β (TGF-β) family member that functions to limit skeletal muscle growth. Accordingly, loss-of-function mutations in myostatin result in a dramatic increase in muscle mass in humans and various animals, while its overexpression leads to severe muscle atrophy. Myostatin also exerts a significant effect on bone metabolism, as demonstrated by enhanced bone mineral density and bone regeneration in myostatin null mice. The identification of myostatin as a negative regulator of muscle and bone mass has sparked an enormous interest in developing myostatin inhibitors as therapeutic agents for treating a variety of clinical conditions associated with musculoskeletal disorders. As a result, various myostatin-targeting strategies involving antibodies, myostatin propeptides, soluble receptors, and endogenous antagonists have been generated, and many of them have progressed to clinical trials. Importantly, most myostatin inhibitors also repress the activities of other closely related TGF-β family members including GDF11, activins, and bone morphogenetic proteins (BMPs), increasing the potential for unwanted side effects, such as vascular side effects through inhibition of BMP 9/10 and bone weakness induced by follistatin through antagonizing several TGF-β family members. Therefore, a careful distinction between targets that may enhance the efficacy of an agent and those that may cause adverse effects is required with the improvement of the target specificity. In this review, we discuss the current understanding of the endogenous function of myostatin, and provide an overview of clinical trial outcomes from different myostatin inhibitors.

The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle

“…A member of the transforming growth factor β superfamily, myostatin is important for the regulation of both pre- and post-natal muscle growth. There is evidence to suggest that through interplay with GDF11, myostatin coordinates muscle growth to ensure a proportionate ratio between skeletal muscle and bone growth rate and density (as reviewed recently in [ 5 ]), such that the skeleton is capable of supporting the musculature and the musculature capable of moving the skeleton. Myostatin is a well-established inhibitor of mRNA translation, i.e., protein synthesis, in part, via targeted suppression of mammalian/mechanistic target of rapamycin complex (mTORC), a highly conserved serine/threonine kinase widely considered to be a master regulator of cell growth [ 6 , 7 , 8 ].…”

“…Despite the lack of translational outcomes for myostatin inhibitors so far, it is important to note that the clinical trials investigating myostatin inhibitors against DMD did not all fail to elicit muscle mass increases. ACE-031 (NCT01099761) and ACE-083 (NCT02927080), domagrozumab (NCT02310763) and RG6206/R07239361 (NCT03039686), all produced mild (generally < 5%), yet statistically significant increases in muscle/lean mass as measured through non-invasive imaging of DMD patients [ 4 , 5 ]. However, what these studies did fail to show were concomitant improvements in strength which should have accompanied these mass gains.…”

“…However, what these studies did fail to show were concomitant improvements in strength which should have accompanied these mass gains. Each of these trials failed to meet either their primary or secondary/surrogate outcome measures concerning muscle function [ 4 , 5 ]. This is important when considered in the context of the endpoint and surrogate outcome measures selected, through which drug efficacy is validated.…”

“…Mechanotransduction occurs through a complex interplay between bone, connective tissue and muscle signalling to ensure muscle and bone growth are synchronous and that tendons are strong enough to facilitate the forces that are exerted on the connection [ 112 ]. In addition to the repression of muscle growth, myostatin exerts control over bone morphogenic proteins (BMPs [ 5 ]; especially BMP2) and fibroblasts to stimulate bone resorption and the synthesis of ECM proteins such as collagen [ 113 ], respectively. One reason for myostatin’s strong repressor function on muscle and bone growth in the face of strong pro-fibrogenic activity might be that tendons grow much slower than either muscle or bone, thus through transiently repressing muscle and bone growth, tendon strengthening can “catch up” to guarantee stability of the bone-tendon-muscle unit [ 112 ].…”

Novel Myostatin-Specific Antibody Enhances Muscle Strength in Muscle Disease Models

“…The aforementioned agents in clinical studies inhibit not only myostatin but also other TGF-β superfamily members, such as GDF11, which has a high sequence similarity with myostatin 18,24,25 . However, the role of GDF11 in muscle growth and strength is poorly understood, and whether the inhibition of GDF11 is bene cial for the treatment of muscle diseases is unclear [26][27][28][29][30] .…”