Impact of prednisone on TGF-?1 and collagen in diaphragm muscle frommdx mice

Abstract

The purpose of this study was to assess the impact of prednisone treatment for 8 weeks on the level of transforming growth factor‐beta 1 (TGF‐β1), hydroxyproline (HYP) concentrations, and level of the mature, nonreducible collagen cross‐link hydroxylysylpyridinoline (HP) in diaphragm muscle from 12‐week‐old mdx mice. Diaphragm muscle from untreated mdx mice had a significantly higher level of TGF‐β1, HYP, and HP cross‐link compared with normal C57BL/10J (control) mice. Prednisone treatment significantly reduced the level of TGF‐β1 and HYP in diaphragm from mdx mice to values similar to control mice, but resulted in a higher level of the HP cross‐link compared with untreated mdx mice. These findings indicate that short‐term treatment of mdx mice with prednisone can attenuate the fibrotic response in diaphragm muscle, possibly by mediating the level of TGF‐β. Although prednisone was beneficial in preventing collagen accumulation, it resulted in a higher level of the HP cross‐link, presumably by decreasing collagen turnover © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 428–432, 2001

Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

“…TGF-β1 is highly upregulated in dystrophic skeletal muscle (19), and the level of TGF-β1 protein is significantly elevated in the mdx diaphragm at 12 weeks of age (20). These cytokines are expressed by inflammatory cells such as macrophages (21) and have been shown to stimulate collagen synthesis (22).…”

Preclinical drug trials in the mdx mouse: Assessment of reliable and sensitive outcome measures

“…2,3,9,25,39 These parameters are also used to successfully evaluate drug interventions, and can validate results from longitudinal non-invasive muscle function testing at completion of the trial. 2,4,8,9,11,15,20,21,26,33,39,45 Collagen-sensitive stains can be used to quantitate the amount of fibrosis in cardiac and skeletal muscles, as shown in Figure 2, and Evans blue dye uptake can also be used to assess muscle cell membrane integrity. 3,19,39,40,42 …”

“…Different treatment protocols, age groups, and endpoints have been used to assess the efficacy of drugs in mdx mice 2–4,6,8,9,11,14–16,20,21,31,33,37,39,42,45 (Table 1). Both trial design and endpoints should also consider data most attractive to the U.S. Food and Drug Administration in moving toward investigational new drug applications for initial human trials.…”

Outside in: The matrix as a modifier of muscular dystrophy

“…With regards to mechanistic effects on TGFβ/myostatin signaling, glucocorticoid steroids are known to reduce TGFβ levels in mdx skeletal muscle [87]. However, chronic dosing of these steroids has a wide array of negative effects, including myostatin activation and consequently muscle atrophy [88].…”