The mechanisms of the widespread production of phosphorylated HSP25 after fatiguing muscle stimulation

Abstract

Summary We already showed a widespread heat shock protein (HSP) response to fatigue of a single hindlimb muscle, responsible for a global adaptive response to an acute localized stress. We also demonstrated that the HSP response resulted from the activation of nerve afferents from the stimulated muscle. However, we did not examine the role played by the different muscle afferents as well as the efferent arm of HSP response. We here measured the changes in phosphorylated HSP25 (pHSP25) levels in resting hindlimb muscles, the diaphragm, kidney, and brain in response to a fatiguing stimulation of one tibialis anterior (TA) muscle which was repeated in five series of experiments: 1) intact muscle innervation, 2) during the selective procaine block of conduction in group IV muscle afferents, 3) after muscle nerve transection to suppress all the sensory messages, under pharmacological blockade of the 4) alpha adrenergic or 5) glutamatergic neurotransmission. The data showed that: 1) the pHSP25 response in hindlimb muscles resulted from the stimulation of both the groups III and IV muscle afferents while the pHSP25 response in the diaphragm, kidney, and brain resulted from the sole activation of the group IV fibres, 2) the blockade of alpha adrenergic, but not that of glutamatergic neurotransmission, suppressed the pHSP25 response in all the explored tissues except the brain. The present study highlights the role played by the groups III and IV muscle afferents in the fatigue-induced pHSP25 response and shows that the sympathetic nerve supply to the muscles and kidney represents the efferent arm of the pHSP25 activation. However, the pHSP25 changes in the brain cannot be explained by the pathways investigated here.

Understanding neuromuscular disorders in chronic fatigue syndrome

“…As already suggested 7 , a downregulation of HSP production in some individuals could be caused by the repetition of exercise bouts at high energetic levels. As cited above, the activation of the group III or IV muscle afferents triggers the HSP production in working and resting muscles as well as in the brain and different organs 17 . It may be hypothesized that the prolonged activation of these muscle afferents by the oxidative stress could induce a reduction of HSP production in patients with ME/CFS.…”

“…Multiple stressors, such as fatiguing muscle contraction, muscle acidosis, hypoxia, ischemia, and ROS, stimulate these muscle afferents 14– 16 . Their activation by muscle fatigue triggers the widespread production of HSPs 17 .…”

Muscle fatigue: general understanding and treatment

“… 55 Interestingly, Jammes et al have reported that a widespread HSP25 response to fatigue in a single hindlimb muscle is responsible for a global adaptive response to acute localized stress and have demonstrated that group III and IV muscle afferents play an important role in the fatigue-induced p-HSP25 response; moreover, the sympathetic nerve supply to the muscles and kidney comprises the efferent arm of the p-HSP25 activation. 56 Skeletal muscle HSP25 has been reported to stabilize muscle structure and repair damaged muscle proteins, 57 as well as to decreases apoptosis in cultured muscle C2C12 cells by inhibiting the intrinsic and extrinsic apoptotic cell death pathway. 58 …”

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

“…When muscle afferents are triggered by muscle fatigue, this triggers the production of heat shock proteins (HSPs) ( 299 ). HSPs protect muscle cells against any deleterious effects of ROS generated during exercise by activation of antioxidants ( 300 , 301 ).…”