Acute effects of high-dose methylprednisolone on diaphragm muscle function.
The time- and dose-dependent effects of acute high-dose corticosteroids on the diaphragm muscle are poorly defined. This study aimed to examine in rabbits the temporal relationships and dose-response effects of acute high-dose methylprednisolone succinate on diaphragmatic contractile and structural properties. Animals were assigned to groups receiving: (1) 80 mg/kg/day methylprednisolone (MP80) intramuscularly for 1, 2, and 3 days; (2) 10 mg/kg/day methylprednisolone (MP10, pulse-dose) for 3 days; or (3) saline (placebo) for 3 days; and (4) a control group. Diaphragmatic in vitro force-frequency and force-velocity relationships, myosin heavy chain (MyHC) isoform protein and mRNA, insulin-like growth factor-1 (IGF-1), muscle atrophy F-box (MAF-box) mRNA, and volume density of abnormal myofibrils were measured at each time-point. MP80 did not affect animal nutritional state or fiber cross-sectional area as assessed in separate pair-fed groups receiving methylprednisolone or saline for 3 days. Compared with control values, MP80 decreased diaphragmatic maximum tetanic tension (Po) by 19%, 24%, and 34% after 1, 2, and 3 days (P < 0.05), respectively, whereas MP10 decreased Po modestly (12%; P > 0.05). Vmax and MyHC protein proportions were unchanged in both the MP80 and MP10 groups. Maximum power output decreased after 2 and 3 days of MP80. Suppression of IGF-1 and overexpression of MAF-box mRNA occurred in both MP groups. Significant myofibrillar disarray was also observed in both MP groups. The decline in Po was significantly associated with the increased volume density of abnormal myofibrils. Thus, very high-dose methylprednisolone (MP80) can produce rapid reductions in diaphragmatic function, whereas pulse-dose methylprednisolone (MP10) produces only modest functional loss.
Sassoon
Catherine S H
CS
Department of Medicine, VA Long Beach Healthcare System, 5901 East 7th Street, Long Beach, California 90822, USA. csassoon@uci.edu
Zhu
Ercheng
E
Pham
H Tony
HT
Nelson
Renee S
RS
Fang
Liwei
L
Baker
Michael J
MJ
Caiozzo
Vincent J
VJ
D000704:Analysis of Variance; D000818:Animals; D003964:Diaphragm / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D018696:Neuroprotective Agents; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D044843:SKP Cullin F-Box Protein Ligases; D018995:Myosin Heavy Chains; D008775:Methylprednisolone