Abstract
Elevated mitochondrial reactive oxygen species (mROS) and an increase in caspase-3 activity are established mechanisms that lead to skeletal muscle atrophy via the upregulation of protein degradation pathways. However, the mechanisms upstream of an increase in mROS and caspase-3 activity in conditions of muscle atrophy have not been identified. Based upon knowledge that an event known as mitochondrial permeability transition (MPT) causes an increase in mROS emission and the activation of caspase-3 via mitochondrial release of cytochrome c, as well as the circumstantial evidence for MPT in some muscle atrophy conditions, we tested MPT as a mechanism of atrophy. Briefly, treating cultured single mouse flexor digitorum brevis (FDB) fibers from adult mice with a chemical inducer of MPT (Bz423) for 24 h caused an increase in mROS and caspase-3 activity that was accompanied by a reduction in muscle fiber diameter that was able to be prevented by inhibitors of MPT, mROS, or caspase-3 (p < 0.05). Similarly, a four-day single fiber culture as a model of disuse caused atrophy that could be prevented by inhibitors of MPT, mROS, or activated caspase-3. As such, our results identify MPT as a novel mechanism of skeletal muscle atrophy that operates through mROS emission and caspase-3 activation.
Highlights
Skeletal muscle atrophy occurs in a wide variety of clinical conditions including aging, neuromuscular diseases, lung disease, cardiovascular disease, kidney disease, and cancer, and is associated with exacerbated health outcomes [1,2,3,4,5,6]
When myofibers were treated for 24 h with 300 nM Bz423 + 5 μM mitoTEMPO or 300 nM Bz423 + 20 μM Ac-ATS010-KE, they showed no change in diameter from pre- to post-treatment, whereas myofibers treated with 300 nM Bz423 again demonstrated a significant decrease in diameter (39.75 ± 10.25 vs. 32.25 ± 7.513 μm, p = 0.04) (Figure 5)
Our results demonstrate that the acute chemical induction of mitochondrial permeability transition (MPT) causes atrophy and increases mitochondrial reactive oxygen species (mROS) and caspase-3 activity in isolated single mouse muscle fibers, while the inhibition of any one of MPT, mROS, or caspase-3 prevents the atrophy noted in this model
Summary
Skeletal muscle atrophy occurs in a wide variety of clinical conditions including aging, neuromuscular diseases, lung disease, cardiovascular disease, kidney disease, and cancer, and is associated with exacerbated health outcomes [1,2,3,4,5,6]. Activated caspase-3 promotes muscle atrophy by cleaving actin from muscle cross-bridges, making it available for subsequent ubiquitination [12], and cleaves negative regulators of the 19S proteasome to allow for an increase in proteasome activity [13]. Despite this knowledge, the mechanisms responsible for the increases in mROS and caspase-3 activity in the context of muscle atrophy have not been fully resolved
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