Abstract
Mutations in Cu/Zn superoxide dismutase (SOD1) are one of the genetic causes of Amyotrophic Lateral Sclerosis (ALS). Although the primary symptom of ALS is muscle weakness, the link between SOD1 mutations, cellular dysfunction and muscle atrophy and weakness is not well understood. The purpose of this study was to characterize cellular markers of ER stress in skeletal muscle across the lifespan of G93A*SOD1 (ALS-Tg) mice. Muscles were obtained from ALS-Tg and age-matched wild type (WT) mice at 70d (pre-symptomatic), 90d and 120–140d (symptomatic) and analyzed for ER stress markers. In white gastrocnemius (WG) muscle, ER stress sensors PERK and IRE1α were upregulated ~2-fold at 70d and remained (PERK) or increased further (IRE1α) at 120–140d. Phospho-eIF2α, a downstream target of PERK and an inhibitor of protein translation, was increased by 70d and increased further to 12.9-fold at 120–140d. IRE1α upregulation leads to increased splicing of X-box binding protein 1 (XBP-1) to the XBP-1s isoform. XBP-1s transcript was increased at 90d and 120–140d indicating activation of IRE1α signaling. The ER chaperone/heat shock protein Grp78/BiP was upregulated 2-fold at 70d and 90d and increased to 6.1-fold by 120–140d. The ER-stress-specific apoptotic signaling protein CHOP was upregulated 2-fold at 70d and 90d and increased to 13.3-fold at 120–140d indicating progressive activation of an apoptotic signal in muscle. There was a greater increase in Grp78/BiP and CHOP in WG vs. the more oxidative red gastrocnemius (RG) ALS-Tg at 120–140d indicating greater ER stress and apoptosis in fast glycolytic muscle. These data show that the ER stress response is activated in skeletal muscle of ALS-Tg mice by an early pre-symptomatic age and increases with disease progression. These data suggest a mechanism by which myocellular ER stress leads to reduced protein translation and contributes to muscle atrophy and weakness in ALS.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease characterized by degeneration of motor neurons and progressive paralysis of skeletal muscle
In this study we show that endoplasmic reticulum (ER) stress is activated in skeletal muscle of G93A*superoxide dismutase 1 (SOD1) mice and may play a role in muscle atrophy in ALS
This is based on evidence that: (i) ER stress is activated at 70d, an early pre-symptomatic age and is further upregulated at 120–140d, an age when mice are symptomatic; (ii) skeletal muscle ER stress induces the cell death signal C/EBP homologous protein (CHOP); (iii) ER stress is activated to a greater extent in highly glycolytic muscles with primarily type IIb fibers which are affected by an early loss of fast fatigable motor axons; and (iv) the ER stress activation is specific to skeletal vs. cardiac muscle
Summary
Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease characterized by degeneration of motor neurons and progressive paralysis of skeletal muscle. Mice generated to express a human Cu/Zn SOD1 mutation found in fALS patients (Gly to Ala; G93A) develop a rapidly progressive and fatal motor neuron disease similar to the clinical phenotype of ALS (Gurney et al, 1994). There is evidence that the SOD1 mutations exert their deleterious effects through a ‘‘gain-of-function’’ mechanism rather than through a loss of superoxide dismutase activity (Yim et al, 1996). The nature of this toxic ‘‘gain-of-function’’ is not known, a number of putative mechanisms have been proposed, including oxidative stress, glutamate-mediated excitotoxicity, mitochondrial dysfunction, protein aggregation and endoplasmic reticulum (ER) stress (Robberecht and Philips, 2013)
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