Long-Term Exercise Protects against Cellular Stresses in Aged Mice

The current study examined the effect of aging and long-term wheel-running on the expression of heat shock protein (HSP), redox
regulation, and endoplasmic reticulum (ER) stress markers in tibialis anterior (T.A.) and soleus muscle of mice. Male mice were
divided into young (Y, 3-month-old), old-sedentary (OS, 24-month-old), and old-exercise (OE, 24-month-old) groups. The OE
group started voluntary wheel-running at 3 months and continued until 24 months of age. Aging was associated with a higher
thioredoxin-interacting protein (TxNiP) level, lower thioredoxin-1 (TRX-1) to TxNiP ratio—a determinant of redox regulation
and increased CHOP, an indicator of ER stress-related apoptosis signaling in both muscles. Notably, GRP78, a key indicator of
ER stress, was selectively elevated in T.A. Long-term exercise decreased TxNiP in T.A. and soleus muscles and increased the
TRX-1/TxNiP ratio in soleus muscle of aged mice. Inducible HSP70 and constituent HSC70 were upregulated, whereas CHOP
was reduced after exercise in soleus muscle. Thus, our data demonstrated that aging induced oxidative stress and activated ER
stress-related apoptosis signaling in skeletal muscle, whereas long-term wheel-running improved redox regulation, ER stress
adaptation and attenuated ER stress-related apoptosis signaling. These findings suggest that life-long exercise can protect against
age-related cellular stress.