Duchenne muscular dystrophy (DMD) is characterized by myofiber death from apoptosis or necrosis, leading in many patients to fatal respiratory muscle weakness. Among other pathological features, DMD muscles show severely deranged metabolic gene regulation and mitochondrial dysfunction. Defective mitochondria not only cause energetic deficiency, but also play roles in promoting myofiber atrophy and injury via opening of the mitochondrial permeability transition pore. Autophagy is a bulk degradative mechanism that serves to augment energy production and eliminate defective mitochondria (mitophagy). We hypothesized that pharmacological activation of AMP-activated protein kinase (AMPK), a master metabolic sensor in cells and on-switch for the autophagy-mitophagy pathway, would be beneficial in the mdx mouse model of DMD. Treatment of mdx mice for 4 weeks with an established AMPK agonist, AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside), potently triggered autophagy in the mdx diaphragm without inducing muscle fiber atrophy. In AICAR-treated mdx mice, the exaggerated sensitivity of mdx diaphragm mitochondria to calcium-induced permeability transition pore opening was restored to normal levels. There were associated improvements in mdx diaphragm histopathology and in maximal force-generating capacity, which were not linked to increased mitochondrial biogenesis or up-regulated utrophin expression. These findings suggest that agonists of AMPK and other inducers of the autophagy-mitophagy pathway can help to promote the elimination of defective mitochondria and may thus serve as useful therapeutic agents in DMD.

Muscle dysfunction is a major problem in chronic obstructive pulmonary disease (COPD), particularly after exacerbations. We thus asked whether neuromuscular electrostimulation (NMES) might be directly useful following an acute exacerbation and if such a therapy decreases muscular oxidative stress and/or alters muscle fibre distribution.A pilot randomised controlled study of NMES lasting 6 weeks was carried out in 15 in-patients (n59 NMES; n56 sham) following a COPD exacerbation. Stimulation was delivered to the quadriceps and hamstring muscles (35 Hz). Primary outcomes were quadriceps force and muscle oxidative stress.At the end of the study, quadriceps force improvement was statistically different between groups (p50.02), with a significant increase only in the NMES group (median (interquartile range) 10 (4.7-11.5) kg; p50.01). Changes in the 6-min walking distance were statistically different between groups (p50.008), with a significant increase in the NMES group (165 (125-203) m; p50.003). NMES did not lead to higher muscle oxidative stress, as indicated by the decrease in total protein carbonylation (p50.02) and myosin heavy chain carbonylation (p50.01) levels. Finally, we observed a significant increase in type I fibre proportion in the NMES group.Our study shows that following COPD exacerbation, NMES is effective in counteracting muscle dysfunction and decreases muscle oxidative stress.

Recently, we have shown implication of Brm, the catalytic subunit of the SWI/SNF chromatin remodeling complex, in repression of cyclin A expression in quiescent cells. Here, we have examined the fate of cells lacking Brm throughout the cycle. We find that despite elevated levels of cyclins A and E, these cells can respond to serum starvation, however, without reaching a canonical G 0 phase as they continue to express high levels of c-Myc and have an abnormally large average size. The response to serum starvation can be correlated with increased levels of Rb proteins p130 and p107 as well as increased association of p27 with the cyclin-dependent kinases, possibly compensating for the higher levels of G 1 cyclins by reducing their associated kinase activity. After serum stimulation, reentry into the cycle occurs normally, but the S phase is delayed and shorter. In addition, the M phase has an increased duration, and we observed frequent faulty chromosome segregation events in anaphase. Altogether, our data suggest that cells can partially overcome the absence of Brm by activating several compensatory mechanisms to control the cell cycle. However, they remain profoundly affected, unable to enter a canonical quiescent state, presenting a shorter S phase, and finally unable to perform correct chromosome segregation. (Cancer Res 2006; 66(10): 5069-76)

The contractile activity of striated muscle depends on myofibrils that are highly ordered macromolecular complexes. The protein components of myofibrils are well characterized, but it remains largely unclear how signaling at the molecular level within the sarcomere and the control of assembly are coordinated. We show that the Rho GTPase TC10 appears during differentiation of human primary skeletal myoblasts and it is active in differentiated myotubes. We identify obscurin, a sarcomere-associated protein, as a specific activator of TC10. Indeed, TC10 binds directly to obscurin via its predicted RhoGEF motif. Importantly, we demonstrate that obscurin is a specific activator of TC10 but not the Rho GTPases Rac and Cdc42. Finally, we show that inhibition of TC10 activity by expression of a dominant-negative mutant or its knockdown by expression of specific shRNA block myofibril assembly. Our findings reveal a novel signaling pathway in human skeletal muscle that involves obscurin and the Rho GTPase TC10 and implicate this pathway in new sarcomere formation.