Disturbances in Calcium Homeostasis Promotes Skeletal Muscle Atrophy: Lessons From Ventilator-Induced Diaphragm Wasting

Abstract

Mechanical ventilation (MV) is often a life-saving intervention for patients in respiratory failure. Unfortunately, a common and undesired consequence of prolonged MV is the development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is commonly labeled “ventilator-induced diaphragm dysfunction” (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a major risk factor for the failure to wean patients from MV; this inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. Although several processes contribute to the development of VIDD, it is clear that oxidative stress leading to the rapid activation of proteases is a primary contributor. While all major proteolytic systems likely contribute to VIDD, emerging evidence reveals that activation of the calcium-activated protease calpain plays a required role. This review highlights the signaling pathways leading to VIDD with a focus on the cellular events that promote increased cytosolic calcium levels and the subsequent activation of calpain within diaphragm muscle fibers. In particular, we discuss the emerging evidence that increased mitochondrial production of reactive oxygen species promotes oxidation of the ryanodine receptor/calcium release channel, resulting in calcium release from the sarcoplasmic reticulum, accelerated proteolysis, and VIDD. We conclude with a discussion of important and unanswered questions associated with disturbances in calcium homeostasis in diaphragm muscle fibers during prolonged MV.

Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

“…Specifically, oxidative stress can elevate proteolysis in three independent ways. First, oxidative stress often results in increased cytosolic free calcium, and elevated cytosolic calcium can activate both calpains and caspase-3 [ 19 , 20 , 37 , 38 ]. Second, redox disturbances can stimulate several transcriptional activators that promote expression of genes involved in proteolysis (i.e., atrogenes) [ 39 , 40 ].…”

“…Mitochondrial calcium overload is often associated with increased mitochondrial ROS production and activation of the mitochondrial permeability transition pore [ 82 , 83 , 84 , 85 ]. Therefore, mitochondrial calcium overload is a proposed mechanism for explaining the mitochondrial dysfunction associated with prolonged muscle inactivity (reviewed in [ 38 ]).…”

Effect of 40 Hz Magnetic Field Application in Posttraumatic Muscular Atrophy Development on Muscle Mass and Contractions in Rats

“…The amplitude and CT parameters of contractions are related to the regulation of the contractile apparatus, and thus to calcium [Berridge et al, 2003]. Although the mechanism behind changes in the twitch durations associated with atrophy is unknown, it has been suggested that atrophy may be involved in the altering of Ca 2+ signaling [Hyatt and Powers, 2020] or the handling of Ca 2+ by Ca 2+ binding proteins [Fitts et al, 1986; Weiss et al, 2010].…”

Mitochondrial Bioenergetics and Turnover during Chronic Muscle Disuse

“…Indeed, moderate influx of Ca 2+ into the organelle is important in facilitating oxidative phosphorylation in muscle mitochondria [143][144][145]. However, the increased levels of mitochondrial ROS that occur with chronic disuse lead to the oxidation of the RyR1, which promotes excessive Ca 2+ leak into the cytosol as well as an overload of Ca 2+ that is taken up by mitochondria [146]. As a result, the elevated levels of Ca 2+ lead to mitochondrial swelling and subsequent release of pro-apoptotic factors, as well as the activation of various proteolytic and apoptotic factors within the cytosol that collectively promote muscle atrophy via DNA fragmentation and myonuclear decay [33].…”