Skeletal muscle fibrosis is a major pathological hallmark of chronic myopathies in which myofibers are replaced by progressive deposition of collagen and other extracellular matrix proteins produced by muscle fibroblasts. Recent studies have shown that in the absence of the endogenous muscle growth regulator myostatin, regeneration of muscle is enhanced, and muscle fibrosis is correspondingly reduced. We now demonstrate that myostatin not only regulates the growth of myocytes but also directly regulates muscle fibroblasts. Our results show that myostatin stimulates the proliferation of muscle fibroblasts and the production of extracellular matrix proteins both in vitro and in vivo. Further, muscle fibroblasts express myostatin and its putative receptor activin receptor IIB. Proliferation of muscle fibroblasts, induced by myostatin, involves the activation of Smad, p38 MAPK and Akt pathways. These results expand our understanding of the function of myostatin in muscle tissue and provide a potential target for anti-fibrotic therapies.Fibroblasts play an important role in the repair response of tissues to injury by secreting extracellular matrix proteins including collagen and growth factors. However, in a variety of disease states, continued fibrosis contributes to the pathological process. In chronic myopathies and muscular dystrophies, fibrosis is considered to be associated with decreased strength and elasticity of muscle and may inhibit the diffusion of nutrients to myofibers (1-3). Identification of factors that regulate fibrosis is an important goal not only in understanding the pathogenesis of muscular dystrophies but also in developing novel therapies to treat these disorders. Several potential future therapies for the muscular dystrophies, including those involving gene and myoblast transfer, may be hampered by significant fibrosis.Myostatin is a highly conserved transforming growth factor-␤ (TGF-␤) 2 family member that is expressed in skeletal muscle, which is also the primary target tissue (4). Deletion of the myostatin gene (MSTN) in mice leads to muscle hypertrophy and hyperplasia with an approximate doubling of muscle mass (4). This function of myostatin, as an endogenous inhibitor of muscle growth, is also conserved in humans, as demonstrated by the identification of a hypermuscular child with a loss-of-function mutation in the myostatin gene (5). One mechanism by which myostatin regulates muscle growth in adult animals appears to be direct inhibition of the proliferation and differentiation of resident muscle precursor cells (6 -8).The potential effect of myostatin inhibition on muscle degenerative diseases has been explored in various animal models. In the absence of myostatin, muscle regenerates more quickly and completely following acute and chronic injury (8, 9). In the mdx mouse, a model of Duchenne and Becker muscular dystrophy, myostatin deletion, or postnatal inhibition increases muscle mass and strength (10 -12). An early observation of mdx/mstn null mice was that the diaphragm muscle of t...

Chronic exercise training elicits adaptations in the heart that improve pump function and confer cardioprotection. To identify molecular mechanisms by which exercise training stimulates this favorable phenotype, a proteomic approach was employed to detect rat cardiac proteins that were differentially expressed or modified after exercise training. Exercise-trained rats underwent six weeks of progressive treadmill training five days/week, 0% grade, using an interval training protocol. Sedentary control rats were age- and weight-matched to the exercise-trained rats. Hearts were harvested at various times (0-72 h) after the last bout of exercise and were used to generate 2-D electrophoretic proteome maps and immunoblots. Compared with hearts of sedentary rats, 26 protein spot intensities were significantly altered in hypertrophied hearts of exercise-trained rats (p <0.05), and 12 spots appeared exclusively on gels from hearts of exercise-trained rats. Immunoblotting confirmed that chronic exercise training, but not a single bout of exercise, elicited a 2.5-fold increase in the abundance of one of the candidate proteins in the heart, a 20 kDa heat shock protein (hsp20) that persisted for at least 72 h of detraining. Thus, exercise training alters the cardiac proteome of the rat heart; the changes include a marked increase in the expression of hsp20.

A higher percentage of IIX MyHC is expected to impart a high speed of shortening to the TA and LCA muscles. The absence of IIX MyHC in muscles with respiratory (PCA) and mixed respiratory/phonatory function (CT) further supports the inference that the physiologic difference between laryngeal muscles is reflected in the molecular composition of contractile protein.