Mitochondrial dysfunction represents the most prevalent inherited metabolic disorder, affecting 1 in 5,000 individuals. Sensory ataxia, a disruption in motor control, is frequently an early symptom of mitochondria dysfunction, leading to an increased risk of falling and associated injury and fears. Mutations causing mitochondrial dysfunction may arise within the mitochondrial genome or nuclear-encoded mitochondrial genes (1). Mitochondria occupy approximately 55% of the volume of sensory terminals in the mouse muscle spindle, making them extraordinarily abundant (2). To investigate their function within muscle spindle primary sensory terminals, we have examined the effects of drugs that interfere with different aspects of mitochondrial activity on the firing of the primary afferents in response to muscle stretching.

Trapezoidal stretch-hold-release extensions (+10% of resting muscle length) were administered every 20 minutes to isolated adult C57/Bl6 mouse soleus muscles ex vivo. Whole nerve responses were recorded, for control, drug and drug washout from the same preparation. We investigated the effects of NH₄Cl (0.5-50 mM), which neutralizes pH in intracellular compartments and regulates mitochondrial biogenesis (3), caffeine (0.1-10 mM), which releases Ca²⁺ from intracellular stores (4), and thapsigargin (0.1-1 μM), which also releases Ca²⁺ from intracellularly stores and, in mitochondria, induces the permeability transition (5).

NH₄Cl (50 mM) abolished stretch-evoked firing in all preparations (n = 5; P < 0.05, paired t-test) within 20 min, indicating great importance of pH in some functional aspect.  Caffeine resulted in a substantial inhibition in firing (1 mM, 63.5 ± 9.5 %, P < 0.05; & 10 mM, 42.9 ± 18.8 %, P < 0.05; n = 11. All data expressed as mean ± SEM). Finally, thapsigargin (0.1, 0.5 & 1.0 μM) tended to produce a dose-dependent decrease (to 48.8 ± 12.5 % at 1 μM) in firing but did not reach significance (n = 7; P = 0.09). All effects were at least partially reversible on drug washout.

In summary, these findings suggest that mitochondrial function significantly influences the capacity of primary afferent mechanosensory terminals to respond to physiological stimuli.