Highlights Muscular contractions stimulate reactive oxygen species production in active muscle fibers and skeletal muscles are a primary source of reactive oxygen species production during exercise. Prolonged or high intensity exercise can result in both: (1) oxidative damage in skeletal muscle fibers and (2) accelerated muscle fatigue. Exercise-induced increases in the production of reactive oxygen species in skeletal muscle plays a required role in skeletal muscle adaptation to endurance training. Based on the available evidence, it appears unlikely that rigorous and prolonged exercise results in an oxidative stress level that is detrimental to human health.

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Intensive care unit (ICU)-acquired weakness is a frequent consequence of critical illness that impacts both the limb and respiratory muscles. The cause of ICU-acquired weakness is multifactorial, but both prolonged limb muscle inactivity and mechanical ventilation are risk factors for muscle wasting, which predisposes ICU patients to both short-term complications and long-term disabilities resulting from muscle weakness. Unfortunately, the current research does not provide a detailed understanding of the cellular etiology of ICU-acquired weakness, and no standard treatment exists. Therefore, improving knowledge of the mechanisms promoting muscle atrophy in critically ill patients is essential to developing therapeutic strategies to protect against ICU-induced skeletal muscle wasting. To advance our understanding of the mechanism(s) responsible for ICU-acquired weakness, we tested the hypothesis that ICU-induced muscle inactivity promotes a rapid decrease in anabolic signaling/protein synthesis and accelerates proteolysis in both limb and respiratory muscles. To investigate ICU-induced changes in skeletal muscle proteostasis, adult Sprague Dawley rats were anesthetized and mechanically ventilated for 12 h to simulate ICU care. Measurements of anabolic signaling, protein synthesis, and proteolytic activity in the limb muscles (plantaris and soleus) and respiratory muscles (parasternal and intercostal) revealed ICU-induced reductions in both anabolic signaling (i.e., AKT/mTOR pathway) and muscle protein synthesis. Moreover, simulated ICU care resulted in increased biomarkers of accelerated proteolysis in both limb and respiratory muscles. These novel findings reveal that disturbances in limb and respiratory muscle proteostasis occur rapidly during ICU-induced muscle inactivity, irrespective of the muscle function or muscle fiber type.

Mechanical ventilation (MV) is a clinical tool that provides respiratory support to patients unable to maintain adequate alveolar ventilation on their own. Although MV is often a life-saving intervention in critically ill patients, an undesired side-effect of prolonged MV is the rapid occurrence of diaphragmatic atrophy due to accelerated proteolysis and depressed protein synthesis. Investigations into the mechanism(s) responsible for MV-induced diaphragmatic atrophy reveal that activation of the calcium-activated protease, calpain, plays a key role in accelerating proteolysis in diaphragm muscle fibers. Moreover, active calpain has been reported to block signaling events that promote protein synthesis (i.e., inhibition of mammalian target of rapamycin (mTOR) activation). While this finding suggests that active calpain can depress muscle protein synthesis, this postulate has not been experimentally verified. Therefore, we tested the hypothesis that active calpain plays a key role in the MV-induced depression of both anabolic signaling events and protein synthesis in the diaphragm muscle. MV-induced activation of calpain in diaphragm muscle fibers was prevented by transgene overexpression of calpastatin, an endogenous inhibitor of calpain. Our findings indicate that overexpression of calpastatin averts MV-induced activation of calpain in diaphragm fibers and rescues the MV-induced depression of protein synthesis in the diaphragm muscle. Surprisingly, deterrence of calpain activation did not impede the MV-induced inhibition of key anabolic signaling events including mTOR activation. However, blockade of calpain activation prevented the calpain-induced cleavage of glutaminyl-tRNA synthetase in diaphragm fibers; this finding is potentially important because aminoacyl-tRNA synthetases play a central role in protein synthesis. Regardless of the mechanism(s) responsible for calpain’s depression of protein synthesis, these results provide the first evidence that active calpain plays an important role in promoting the MV-induced depression of protein synthesis within diaphragm fibers.

Doxorubicin (DOX) is a chemotherapeutic agent highly effective at limiting cancer progression. Despite the efficacy of this anticancer drug, the clinical use of DOX is limited due to cardiotoxicity. The cardiac mitochondria are implicated as the primary target of DOX, resulting in inactivation of electron transport system complexes, oxidative stress, and iron overload. However, it is established that the cardiac mitochondrial subpopulations reveal differential responses to DOX exposure, with subsarcolemmal (SS) mitochondria demonstrating redox imbalance and the intermyofibrillar (IMF) mitochondria showing reduced respiration. In this regard, exercise training is an effective intervention to prevent DOX-induced cardiac dysfunction. Although it is clear that exercise confers mitochondrial protection, it is currently unknown if exercise training mitigates DOX cardiac mitochondrial toxicity by promoting beneficial adaptations to both the SS and IMF mitochondria. To test this, SS and IMF mitochondria were isolated from sedentary and exercise-preconditioned female Sprague Dawley rats exposed to acute DOX treatment. Our findings reveal a greater effect of exercise preconditioning on redox balance and iron handling in the SS mitochondria of DOX-treated rats compared to IMF, with rescue of cardiolipin synthase 1 expression in both subpopulations. These results demonstrate that exercise preconditioning improves mitochondrial homeostasis when combined with DOX treatment, and that the SS mitochondria display greater protection compared to the IMF mitochondria. These data provide important insights into the molecular mechanisms that are in part responsible for exercise-induced protection against DOX toxicity.