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Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy and physiological and molecular impacts of T therapy adjuvant to short\u2010term RET remain poorly defined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eighteen non\u2010hypogonadal healthy older men, 65\u201375 years, were assigned in a random double\u2010blinded fashion to receive, biweekly, either placebo (P, saline, <jats:italic>n<\/jats:italic> = 9) or T (Sustanon 250 mg, <jats:italic>n<\/jats:italic> = 9) injections over 6 week whole\u2010body RET (three sets of 8\u201310 repetitions at 80% one\u2010repetition maximum). Subjects underwent dual\u2010energy X\u2010ray absorptiometry, ultrasound of vastus lateralis (VL) muscle architecture, and knee extensor isometric muscle force tests; VL muscle biopsies were taken to quantify myogenic\/anabolic gene expression, anabolic signalling, muscle protein synthesis (D<jats:sub>2<\/jats:sub>O), and breakdown (extrapolated).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Testosterone adjuvant to RET augmented total fat\u2010free mass (<jats:italic>P=<\/jats:italic>0.007), legs fat\u2010free mass (<jats:italic>P=<\/jats:italic>0.02), and appendicular fat\u2010free mass (<jats:italic>P=<\/jats:italic>0.001) gains while decreasing total fat mass (<jats:italic>P=<\/jats:italic>0.02). Augmentations in VL muscle thickness, fascicle length, and quadriceps cross\u2010section area with RET occured to a greater extent in T (<jats:italic>P<\/jats:italic> &lt; 0.05). Sum strength (<jats:italic>P=<\/jats:italic>0.0009) and maximal voluntary contract (e.g. knee extension at 70\u00b0) (<jats:italic>P=<\/jats:italic>0.002) increased significantly more in the T group. Mechanistically, both muscle protein synthesis rates (T: 2.13 \u00b1 0.21%\u00b7day<jats:sup>\u22121<\/jats:sup> vs. P: 1.34 \u00b1 0.13%\u00b7day<jats:sup>\u22121<\/jats:sup>, <jats:italic>P=<\/jats:italic>0.0009) and absolute breakdown rates (T: 140.2 \u00b1 15.8 g\u00b7day<jats:sup>\u22121<\/jats:sup> vs. P: 90.2 \u00b1 11.7 g\u00b7day<jats:sup>\u22121<\/jats:sup>, <jats:italic>P=<\/jats:italic>0.02) were elevated with T therapy, which led to higher net turnover and protein accretion in the T group (T: 8.3 \u00b1 1.4 g\u00b7day<jats:sup>\u22121<\/jats:sup> vs. P: 1.9 \u00b1 1.2 g\u00b7day<jats:sup>\u22121<\/jats:sup>, <jats:italic>P=<\/jats:italic>0.004). Increases in ribosomal biogenesis (RNA:DNA ratio); mRNA expression relating to T metabolism (androgen receptor: 1.4\u2010fold; <jats:italic>Srd5a1<\/jats:italic>: 1.6\u2010fold; <jats:italic>AKR1C3<\/jats:italic>: 2.1\u2010fold; and <jats:italic>HSD17\u03b23<\/jats:italic>: two\u2010fold); insulin\u2010like growth factor (IGF)\u20101 signalling [<jats:italic>IGF\u20101Ea<\/jats:italic> (3.5\u2010fold) and <jats:italic>IGF\u20101Ec<\/jats:italic> (three\u2010fold)] and myogenic regulatory factors; and the activity of anabolic signalling (e.g. mTOR, AKT, and RPS6; <jats:italic>P<\/jats:italic> &lt; 0.05) were all up\u2010regulated with T therapy. Only T up\u2010regulated mitochondrial citrate synthase activity (<jats:italic>P=<\/jats:italic>0.03) and transcription factor A (1.41 \u00b1 0.2\u2010fold, <jats:italic>P=<\/jats:italic>0.0002), in addition to peroxisome proliferator\u2010activated receptor\u2010\u03b3 co\u2010activator 1\u2010\u03b1 mRNA (1.19 \u00b1 0.21\u2010fold, <jats:italic>P=<\/jats:italic>0.037).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Administration of T adjuvant to RET enhanced skeletal muscle mass and performance, while up\u2010regulating myogenic gene programming, myocellular translational efficiency and capacity, collectively resulting in higher protein turnover, and net protein accretion. T coupled with RET is an effective short\u2010term intervention to improve muscle mass\/function in older non\u2010hypogonadal men.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12472","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T05:30:22Z","timestamp":1569907822000},"page":"1276-1294","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men"],"prefix":"10.1002","volume":"10","author":[{"given":"Nima","family":"Gharahdaghi","sequence":"first","affiliation":[{"name":"MRC\u2010ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine University of Nottingham, Derby  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supreeth","family":"Rudrappa","sequence":"additional","affiliation":[{"name":"MRC\u2010ARUK Centre 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