SKELETAL MUSCLE MITOCHONDRIAL ALTERATIONS IN CARBOXYL TERMINUS OF HSC70 INTERACTING PROTEIN (CHIP) -/- MICE.

AIM

Hereditary ataxias are characterized by a slowly progressive loss of gait, hand, speech, and eye coordination and cerebellar atrophy. A subset of these, including hypogonadism, are inherited as autosomal recessive traits involving coding mutations of genes involved in ubiquitination including , and . Cerebellar CHIPopathy (MIM 615768) is a form of autosomal recessive spinocerebellar ataxia (SCAR16) and when accompanied with hypogonadism, clinically resembles the Gordon Holmes Syndrome (GHS). A causal missense mutation in the gene that encodes the carboxy terminus of HSP-70 interacting protein (CHIP) protein was reported for the first time in 2014. CHIP-/- mice were found to phenocopy the motor deficiencies and some aspects of the hypogonadism observed in patients with mutations. However, mechanisms responsible for these deficits are not known.

METHODS

In a survey of skeletal muscle by transmission electron microscopy.

RESULTS

CHIP-/- mice at 6 months of age were found to have morphological changes consistent with increased sarcoplasmic reticulum compartments in quadriceps muscle and gastrocnemius (toxic oligomers and tubular aggregates), but not in soleus.

CONCLUSION

Since CHIP has been implicated in ER stress in non-muscle cells, these findings illustrate potential parallel roles of CHIP in the muscle sarcoplasmic reticulum, a hypothesis that may be clinically relevant in a variety of common muscular and cardiac diseases.