Myostatin regulation during skeletal muscle regeneration

Abstract

Myostatin, a member of the TGF-beta superfamily, is a key negative regulator of skeletal muscle growth. The role of myostatin during skeletal muscle regeneration has not previously been reported. In the present studies, normal Sprague-Dawley and growth hormone (GH)-deficient (dw/dw) rats were administered the myotoxin, notexin, in the right M. biceps femoris on day 0. The dw/dw rats then received either saline or human-N-methionyl GH (200microg/100g body weight/day) during the ensuing regeneration. Normal and dw/dw M. biceps femoris were dissected on days 1, 2, 3, 5, 9 and 13, formalin-fixed, then immunostained for myostatin protein. Immunostaining for myostatin revealed high levels of protein within necrotic fibres and connective tissue of normal and dw/dw damaged muscles. Regenerating myotubes contained no myostatin at the time of fusion (peak fusion on day 5), and only low levels of myostatin were observed during subsequent myotube enlargement. Fibres which survived assault by notexin (survivor fibres) contained moderate to high myostatin immunostaining initially. The levels in both normal and dw/dw rat survivor fibres decreased on days 2-3, then increased on days 9-13. In dw/dw rats, there was no observed effect of GH administration on the levels of myostatin protein in damaged muscle. The low level of myostatin observed in regenerating myotubes in these studies suggests a negative regulatory role for myostatin in muscle regeneration.

Characterization of GHRs, IGFs and MSTNs, and analysis of their expression relationships in blunt snout bream, Megalobrama amblycephala

“…Nevertheless, some studies into the relationship between GH and MSTNs might further elucidate this complex relationship. An inverse relationship between GH and MSTN was found in rat muscle (Kirk et al, 2000) and human muscle cells (Taylor et al, 2001). Some researchers also found that a GH-responsive element was identified to be the upstream of the MSTN promoter region in fish (Roberts and Goetz, 2003;Taylor et al, 2001), which suggested that at the same time GH could regulate MSTN gene transcription and stimulate the GHR gene expression.…”

BAF60 A, B, and Cs of muscle determination and renewal

“…For instance, transforming growth factor-b (TGFb) family members control diverse processes in the myoblast and satellite cells ranging from proliferation and fusion to differentiation, and the patterns of expression change dynamically in regenerating muscles to control sequential stages of muscle repair (Kollias and McDermott 2008). Illustrating a switch from an adaptive to a maladaptive mechanism, functional levels of the TGFb family member myostatin, a negative regulator of muscle mass, decline during active regeneration to permit satellite cell activation (Kirk et al 2000;Kocamis et al 2001). However, in chronic myopathic states, myostatin as well as TGFb itself are elevated coincident with fibrosis, and recent interventions to antagonize signaling have been noted to restore muscle function in mouse models of muscular dystrophies (Minetti et al 2006;Cohn et al 2007).…”

Human Sarcopenia Reveals an Increase in SOCS-3 and Myostatin and a Reduced Efficiency of Akt Phosphorylation

“…61 The increase in skeletal muscle myostatin protein levels may be linked with myofiber necrosis, as myostatin levels have been shown to be elevated within necrotic, but not regenerating fibers. 62 Additionally, increased levels of myostatin may contribute to reduced myofiber regenerative potential 58 by inhibiting myoblast proliferation. 63 Future investigations should be aimed at establishing if the alterations in signaling proteins observed in the present study are also implicated in other abnormalities occurring in aged skeletal muscle.…”