Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function

Ultrastructural studies have previously suggested potential association of intermediate filaments (IFs) with mitochondria. Thus, we have investigated mitochondrial distribution and function in muscle lacking the IF protein de smin, Immunostaining of skeletal muscle tissue sections. as well as histoch emical staining for the mitochondrial marker enzymes cytochrome C oxidase a nd succinate dehydrogenase, demonstrate abnormal accumulation of subsarcole mmal clumps of mitochondria in predominantly slow twitch skeletal muscle of desmin-null mice. Ultrastructural observation of desmin-null cardiac muscl e demonstrates in addition to clumping, extensive mitochondrial proliferati on in a significant fraction of the myocytes, particularly after work overl oad. These alterations are frequently associated with swelling and degenera tion of the mitochondrial matrix. Mitochondrial abnormalities can be detect ed very early before other structural defects become obvious. To investigat e related changes in mitochondrial function, we have analyzed ADP-stimulate d respiration of isolated muscle mitochondria, and ADP-stimulated mitochond rial respiration in situ using saponin skinned muscle fibers. The in vitro maximal rates of respiration in isolated cardiac mitochondria from desmin-n ull and wild-type mice were similar. However, mitochondrial respiration in situ is significantly altered in desmin-null muscle. Both the maximal rate of ADP-stimulated oxygen consumption and the dissociation constant (K-m) fo r ADP are significantly reduced in desmin-null cardiac and soleus muscle co mpared with controls. Respiratory parameters for desmin-null fast twitch ga strocnemius muscle were unaffected. Additionally, respiratory measurements in the presence of creatine indicate that coupling of creatine kinase and t he adenine translocator is lost in desmin-null soleus muscle. This coupling is unaffected in cardiac muscle from desmin-null animals. All of these stu dies indicate that desmin IFs play a significant role in mitochondrial posi tioning and respiratory function in cardiac and skeletal muscle.