Glucose uptake and utilization are also controlled by the ECM and myostatin may also modulate glucose metabolism indirectly through increasing collagen deposition within the ECM [83] (Determine 3A). standard of care corticosteroid treatment in DMD patients which was never extensively tested in pre-clinical animal trials. These factors are explored in detail herein, in context of the known cellular pathophysiological events that drive DMD. We also discuss other potential factors which might alternatively explain the failed translation of myostatin inhibitor drugs, such as the important regulatory role myostatin plays on metabolism and the important role electrical stimulation plays in mechanotransduction signalling of muscle growth during myostatin inhibition, with important implications for future drug development programs. 2. Myostatin Is usually Differentially Expressed in Mice and Humans Myostatin negatively controls skeletal muscle growth and quality through multiple molecular mechanisms. A member of the transforming growth factor superfamily, myostatin is usually 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 CD300E ensure a proportionate ratio between skeletal muscle and bone growth rate and density (as reviewed recently in [5]), such that the skeleton is usually capable of supporting the musculature and the musculature capable of moving the skeleton. Myostatin is usually 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 grasp regulator of cell growth [6,7,8]. Additionally, myostatin drives atrophy through pro-degradative signal-transduction mechanisms in a Smad2/3-dependent manner, increasing FoxO transcriptional activity and upregulating the expression of E3-ubiquitin ligases [8,9]. Collectively, these mechanisms account for most of myostatins activity against post-natal muscle growth. In this regard, myostatin may act as an environmental sensor/signaler of nutritional status (particularly in a low amino acid environment) [10] in synergy with the cellular energy sensor, adenosine monophosphate-activated protein kinase (AMPK) [11], promoting a negative feedback loop that inhibits ribosomal biogenesis and, subsequently, mTOR-dependent protein synthesis [12,13,14]. Myostatin is also a negative regulator of muscle stem satellite cell proliferation and differentiation at the G1 to S progression phase of mitosis, which maintains satellite cells in a quiescent state [15]. While strong repressor activity of satellite cell proliferation and differentiation through Smad 2/3 signaling may account for 360A a proportion of myostatins role in post-natal muscle growth inhibition, myostatin is probably most influential around the regulation of embryonic muscle progenitors during pre-natal muscle growth where its role remains controversial. Embryonic muscle 360A growth is usually both hyperplastic and hypertrophic: that is, muscle tissue growth involves both increased myofibre number via the accretion of myoblasts myotubes myofibres, followed by their relative diametric and longitudinal growth, which is usually equally dependent upon motor neuron outgrowth and functional innervation [16]. Usually by 7 years of age, hyperplastic muscle growth ceases and, thereafter, only hypertrophic growth is responsible for increased muscle size [17]this is usually achieved through protein synthesis, which is dependent upon the genetic material donated through satellite-cell dependent myotube fusion [18]. Myostatin is usually strongly expressed in embryonic somites where it appears to modulate the balance between proliferation and differentiation of muscle progenitors during development [19], possibly by sensitizing them to pro-differentiation signals (e.g., Notch signaling [20,21]). In this manner, myostatin helps to set both the finite myofibre number as well as the extent of the satellite cell pool, 360A which dictates the capacity for post-natal growth. This is in direct contrast to its strong repressor activity on post-natal muscle growth. Thus, myostatin apparently exerts very different effects on skeletal muscle growth in the embryonic.