Abstract
We explored the interrelationship between a tissue-specific alternative splicing factor muscleblind-like 1 (MBNL1) and peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α), B-cell lymphoma 2 (Bcl-2) or Bcl-2-associated X protein (Bax) in C2C12 myotubes and mouse skeletal muscle to investigate a possible physiological role of MBNL1 in mitochondrial-associated apoptosis of skeletal muscle. Expression level of PGC-1α and mitochondrial membrane potential evaluated by the fluorescence ratio of JC-1 aggregate to monomer in C2C12 myotubes were suppressed by knockdown of MBNL1. Conversely, the ratio of Bax to Bcl-2 as well as the apoptotic index in C2C12 myotubes was increased by MBNL1 knockdown. In plantaris muscle, on the other hand, not only the minimum muscle fiber diameter but also the expression level of MBNL1 and PGC-1α in of 100-week-old mice were significantly lower than that of 10-week-old mice. Furthermore, the ratio of Bax to Bcl-2 in mouse plantaris muscle was increased by aging. These results suggest that MBNL1 may play a key role in aging-associated muscle atrophy accompanied with mitochondrial dysfunction and apoptosis via mediating PGC-1α expression in skeletal muscle.
Highlights
Skeletal muscle atrophy, which is defined as a loss of muscle mass, is induced by inactivity [1,2,3], disease [4,5,6], or aging [7,8,9]
We investigated the interrelationship between muscleblind-like 1 (MBNL1) and PGC-1α, Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), or mitochondrial membrane potential in C2C12 myotubes and mouse skeletal muscle
Both mRNA and protein expression level of MBNL1 in C2C12 myotubes was decreased by knockdown of MBNL1
Summary
Skeletal muscle atrophy, which is defined as a loss of muscle mass, is induced by inactivity [1,2,3], disease [4,5,6], or aging [7,8,9]. Several hypotheses have been proposed as a cause of age-associated skeletal muscle atrophy, such as proteostasis disruption [11], mitochondrial dysfunction [12], and apoptosis [13]. Activation of apoptosis as well as the upregulation of mitochondrial apoptosis-regulatory proteins including B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) has been reported in aged skeletal muscle [14]. It has been reported that the increase in ratio of Bax to Bcl-2 in skeletal muscle induces mitochondrial apoptosis [9,14,26]. PGC-1α may be a key molecule in age-associated mitochondrial dysfunction as well as apoptosis. We investigated the interrelationship between MBNL1 and PGC-1α, Bax, Bcl-2, or mitochondrial membrane potential in C2C12 myotubes and mouse skeletal muscle. We explored the putative of MBNL1 in mitochondrial-associated apoptosis in skeletal muscle
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