Physical activity guidelines recommend both endurance and resistance exercise to improve and maintain overall health. Recently, progressive weighted wheel running (PoWeR), a voluntary, progressive, and high-volume exercise paradigm, was posited as a singular prototype of combined endurance and resistance exercise in mice as evident by enhanced capillarization and hypertrophy of select plantar flexor muscles. Despite growing interest in this model, it remains incompletely characterized if PoWeR resembles the acute and chronic responses to resistance and/or endurance exercise in humans. Therefore, the purpose of this study was to assess canonical signaling events, mitochondrial bioenergetics, and cellular adaptations across multiple extensor and flexor muscles of the fore- and hindlimbs that may be conducive for whole-body functional improvements as traditionally observed in humans. Eight weeks of PoWeR (∼8 km/day) improved glucose metabolism, exercise capacity, body composition, and bone mineral density as well as increased mass, myofiber cross-sectional area (CSA), and oxidative myofiber type distribution in the soleus, plantaris, and flexor digitorum longus (FDL). Using two ex vivo high-resolution fluororespirometry protocols that model in vivo physiological conditions, PoWeR decreased mitochondrial ADP sensitivity which was accompanied by greater mitochondrial H(2)O(2) emissions, respiration, conductance, and protein content in the vastus lateralis, gastrocnemius, and triceps in muscle-specific fashion. Three days of short-term PoWeR stimulated mTOR complex 1 (mTORC1) and AMP activated protein kinase (AMPK) signaling in soleus, plantaris, and/or FDL in line with the hypertrophic and metabolic adaptations observed with long-term training. Collectively, these data support PoWeR as a suitable paradigm in mice to model the acute signaling and chronic adaptations associated with endurance and resistance exercise in humans.NEW & NOTEWORTHY Using PoWeR, we evaluated skeletal muscle mitochondrial and hypertrophic adaptions revealing muscle-specific adaptations across fore and hind limbs consistent with endurance and resistance exercise in humans. We present a short-term PoWeR paradigm that identifies muscle-specific signaling responses thought to support long-term adaptions to PoWeR. These data provide further support for PoWeR as a model to resemble the metabolic and anabolic adaptions to endurance and resistance exercise in humans.