title: Proteome-wide muscle protein fractional synthesis rates predict muscle mass gain in response to a selective androgen receptor modulator in rats.
abstract: Biomarkers of muscle protein synthesis rate could provide early data demonstrating anabolic efficacy for treating muscle-wasting conditions. Androgenic therapies have been shown to increase muscle mass primarily by increasing the rate of muscle protein synthesis. We hypothesized that the synthesis rate of large numbers of individual muscle proteins could serve as early response biomarkers and potentially treatment-specific signaling for predicting the effect of anabolic treatments on muscle mass. Utilizing selective androgen receptor modulator (SARM) treatment in the ovariectomized (OVX) rat, we applied an unbiased, dynamic proteomics approach to measure the fractional synthesis rates (FSR) of 167-201 individual skeletal muscle proteins in triceps, EDL, and soleus. OVX rats treated with a SARM molecule (GSK212A at 0.1, 0.3, or 1 mg/kg) for 10 or 28 days showed significant, dose-related increases in body weight, lean body mass, and individual triceps but not EDL or soleus weights. Thirty-four out of the 94 proteins measured from the triceps of all rats exhibited a significant, dose-related increase in FSR after 10 days of SARM treatment. For several cytoplasmic proteins, including carbonic anhydrase 3, creatine kinase M-type (CK-M), pyruvate kinase, and aldolase-A, a change in 10-day FSR was strongly correlated (r(2) = 0.90-0.99) to the 28-day change in lean body mass and triceps weight gains, suggesting a noninvasive measurement of SARM effects. In summary, FSR of multiple muscle proteins measured by dynamics of moderate- to high-abundance proteins provides early biomarkers of the anabolic response of skeletal muscle to SARM.
authors.affiliation: KineMed, Inc., Emeryville, California;
authors.forename: Mahalakshmi
authors.initials: M
authors.lastname: Shankaran
authors.affiliation: Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina; and.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Shearer
authors.affiliation: Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina; and.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stimpson
authors.affiliation: KineMed, Inc., Emeryville, California;
authors.forename: Scott M
authors.initials: SM
authors.lastname: Turner
authors.affiliation: KineMed, Inc., Emeryville, California;
authors.forename: Chelsea
authors.initials: C
authors.lastname: King
authors.affiliation: KineMed, Inc., Emeryville, California;
authors.forename: Po-Yin Anne
authors.initials: PY
authors.lastname: Wong
authors.affiliation: Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina; and.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Turnbull
authors.affiliation: Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina; and.
authors.forename: Fritz
authors.initials: F
authors.lastname: Kramer
authors.affiliation: Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina; and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Clifton
authors.affiliation: Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina; and.
authors.forename: Alan
authors.initials: A
authors.lastname: Russell
authors.affiliation: KineMed, Inc., Emeryville, California; Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, California.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
authors.affiliation: KineMed, Inc., Emeryville, California; Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, North Carolina; and wevans@kinemed.com.
authors.forename: William J
authors.identifier: http://orcid.org/0000-0001-6757-1471
authors.initials: WJ
authors.lastname: Evans
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001823:Body Composition; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D052283:Creatine Kinase, MM Form / Q000378:metabolism; D003903:Deuterium; D005260:Female; D013058:Mass Spectrometry; D009124:Muscle Proteins / Q000096:biosynthesis / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D009929:Organ Size; D010052:Ovariectomy; D014176:Protein Biosynthesis / Q000187:drug effects*; D020543:Proteome / Q000096:biosynthesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: D000728:Androgens; D009124:Muscle Proteins; D020543:Proteome; D011944:Receptors, Androgen; D003903:Deuterium; D052283:Creatine Kinase, MM Form
keywords: anabolism; biomarkers of muscle anabolism; dynamic proteomics; fractional synthesis rate; protein synthesis; selective androgen receptor modulator; skeletal muscle; stable isotope