Glucocorticoids are growth-inhibiting steroids. They have been reported to reduce
muscle growth by reducing protein synthesis. However, their actions on muscle protein
degradation remain equivocal. Glucocorticoids have been reported to transiently increase
muscle protein degradation, to not affect this process and to reduce muscle protein
degradation. Reasons for these conflicting reports are not understood but may be related
to species, glucocorticoid doses and route and duration of administration.
Dexamethasone is a synthetic glucocorticoid and is not rapidly metabolized in vivo.
As an inflammatory agent, dexamethasone is more potent than natural glucocorticoids.
The objective of this study was to clarify the role in molecular regulation of calpain
expression as a proteolytic catalyst linked to initiation of myofibrillar protein degradation
by using glucocorticoid-dependent changes in muscle protein degradation as a model. A
secondary objective of investigating molecular mechanisms responsible for regulation of
calpain expression was conducted by examining effects of a synthetic glucocorticoid --dexamethasone
on calpains and calpastatin activities and steady-state mRNA
concentrations encoding these proteins.
Female New Zealand White rabbits (1.8-2.1 kg) were treated with 1 mg
dexamethasone/kg BW/day for 0 day, 1 day, 2 days or 4 days by daily subcutaneous
injection. Cranial biceps femoris were taken for analysis of muscle protein concentration,
muscle RNA concentration, ribosomal capacity, N'-methylhistidine (NMH) concentration
and calpains and calpastatin activities. Because glucocorticoids may mediate their actions
indirectly via other hormones, temporal effects of dexamethasone on plasma T3 and T4
concentrations were also examined.
Dexamethasone transiently decreased (P < .05) final body weight and total body
weight gain in the 1-day dexamethasone-treated rabbits, but food intake was maintained
in both control and dexamethasone-treated rabbits (P > .05). Muscle protein
concentration was unaffected (P > . 05) by dexamethasone, while dexamethasone
decreased (P < .05) muscle RNA concentration in the 4-day dexamethasone-treated
rabbits and tended to decrease ribosomal capacity (P > . 05) gradually as duration of
dexamethasone treatment increased.
Although urinary NMH excretion, which serves as an index of myofibrillar protein
degradation, was not affected by dexamethasone (P > .05), the ratio of urinary NMH
excretion to urinary creatinine output was reduced significantly (P < .05) by 4 days of
dexamethasone treatment compared to 1 day of dexamethasone treatment. Also, muscle
NMH concentration was reduced (P < .05) by dexamethasone treatment. These data
indicate that dexamethasone treatment may have reduced muscle protein degradation.
Calpain I, calpain II and calpastatin activities were not affected by dexamethasone
(P > . 05) although both calpain I and calpain II activities tended to decrease and
calpastatin activity had a tendency to increase as duration of dexamethasone treatment
increased. Maximum effects of dexamethasone on both calpains, urinary NMH excretion
and muscle NMH concentration were detected following 2 days of administration. These
results indicated that the temporal decrease in rabbit skeletal muscle protein degradation
by dexamethasone was related to calpains and calpastatin. mRNA concentrations
encoding calpain I increased (P < .05) in the 1-day dexamethasone-treated rabbits, while
mRNA concentrations encoding calpain II decreased (P < .05). These results imply that
dexamethasone can affect calpain I and calpain II gene expression in an opposing manner
(up-regulation and down-regulation).
Plasma T₃ concentration but not plasma T₄ concentration was significantly reduced
(P < . 05) by dexamethasone treatment. Because T₃ stimulates myofibrillar protein
degradation, its lower concentration in dexamethasone-treated rabbits may account for
the apparent reduction in protein degradation caused by dexamethasone.
In this study, the observed effects of dexamethasone on muscle protein degradation
may be the combination of direct and indirect responses. Thus, in vitro studies will be
needed in order to clarify the direct effects of dexamethasone on muscle protein
degradation. / Graduation date: 1991
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/38115 |
| Date | 04 September 1990 |
| Creators | Yeh, Jan-ying |
| Contributors | Forsberg, Neil E. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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