Oxandrolone enhances skeletal muscle myosin synthesis and alters global gene expression profile in Duchenne muscular dystrophy.
Earlier studies have shown that the progressive, unrelenting muscle loss associated with Duchenne muscular dystrophy (DMD) involves an imbalance between the rates of synthesis and degradation of muscle proteins. Although previous studies have suggested that oxandrolone may be beneficial in DMD, the mechanism of action of oxandrolone on muscle in DMD remains unclear. To address these issues, we combined stable isotope studies and gene expression analysis to measure the fractional synthesis rate of myosin heavy chain (MHC), the key muscle contractile protein, the transcript levels of the isoforms of MHC, and global gene expression profiles in four children with DMD before and after 3 mo of treatment with oxandrolone. Gastrocnemius muscle biopsies and blood samples were collected during the course of a primed 6-h continuous infusion of l-[U-(13)C]leucine on two separate occasions, before and after the 3-mo treatment with oxandrolone (0.1 mg.kg(-1).day(-1)). Gene expression analysis was done with microarrays and RT-qPCR. In response to the treatment, MHC synthesis rate increased 42%, and this rise was accounted for, at least in part, by an upregulation of the transcript for MHC8 (perinatal MHC). Gene expression data suggested a decrease in muscle regeneration as a consequence of oxandrolone therapy, presumably because of a decrease in muscle degeneration. These findings suggest that 1) oxandrolone has a powerful protein anabolic effect on a key contractile protein and 2) larger and longer-term studies are warranted to determine whether these changes translate into meaningful therapy for these patients.
Balagopal
Prabhakaran
P
Nemours Children's Clinic, Jacksonville, FL 32207, USA. bbalagop@nemours.org
Olney
Robert
R
Darmaun
Dominique
D
Mougey
Edward
E
Dokler
Maryann
M
Sieck
Gary
G
Hammond
David
D
D000293:Adolescent; D000418:Albumins / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology*; D002648:Child; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007930:Leucine / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010074:Oxandrolone / Q000494:pharmacology*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024744:Skeletal Muscle Myosins / Q000096:biosynthesis* / Q000235:genetics
D000418:Albumins; D000728:Androgens; D020033:Protein Isoforms; D012333:RNA, Messenger; D010074:Oxandrolone; D024744:Skeletal Muscle Myosins; D018995:Myosin Heavy Chains; D007930:Leucine