Taken together, these data suggest that both the apoptosis and autophagy catabolic pathways might be involved in the muscle atrophy phenotype.
Collectively these findings highlight FoxO as a critical factor controlling diverse transcriptional networks in skeletal muscle during cancer cachexia, which provides novel insight into additional mechanisms whereby the FoxO transcription factors may orchestrate the muscle atrophy phenotype.
We next focused on muscle pathology, since muscle cramping and atrophy are prominent symptoms in SBMA patients (Rhodes et al., 2009; Katsuno et al., 2012), and this SBMA mouse model shows an obvious muscle atrophy phenotype (Cortes et al., 2014; Lieberman et al., 2014).
Symptomatic HD patients exhibit pronounced weight loss and muscle atrophy [17], [27], phenotypes that are modelled in both the R6/2 and HdhQ150 mouse models of HD [10], [13], [28], [29].
Strikingly, in addition to rescuing the muscle atrophy and motor neuron phenotypes, loss of one copy of Nlk extended the lifespan of the BAC fxAR121 +/− mice.
However, due to the concomitant motor involvement with distal muscle atrophy and weakness, this phenotype was originally classified as HMSN (Kwon et al., 1995).
Our group has previously shown that blood microRNA profile reflects muscle phenotype and muscle atrophy in chronic obstructive pulmonary disease (COPD) [ 12, 13].
In contrast, overt phenotypes such as muscle atrophy, tremors, gait defects and growth retardation have been used to signpost abnormal neuromuscular function in mice (4, 5).
Skeletal muscle specific inhibition of autophagy using mice deficient in Atg7 has resulted in a phenotype similar to sarcopenia: muscle atrophy, loss of force, accumulation of abnormal mitochondria, protein aggregates, oxidative stress and apoptosis [ 32, 33].
These mice recapitulate key SBMA disease phenotypes, including motor neuron pathology, muscle atrophy, and early lethality.
