Altered mitochondrial morphology and defective protein import reveal novel roles for Bax and/or Bak in skeletal muscle.

The function Bax and/or Bak in constituting a gateway for mitochondrial apoptosis in response to apoptotic stimuli has been unequivocally demonstrated. However, recent work has suggested that Bax/Bak may have unrecognized nonapoptotic functions related to mitochondrial function in nonstressful environments. Wild-type (WT) and Bax/Bak double knockout (DKO) mice were used to determine alternative roles for Bax and Bak in mitochondrial morphology and protein import in skeletal muscle.

The effects of chronic muscle use and disuse on cardiolipin metabolism.

Cardiolipin (CL) is a phospholipid that maintains the integrity of mitochondrial membranes. We previously demonstrated that CL content increases with chronic muscle use, and decreases with denervation-induced disuse. To investigate the underlying mechanisms, we measured the mRNA expression of 1) CL synthesis enzymes cardiolipin synthase (CLS) and CTP:PA-cytidylyltransferase-1 (CDS-1); 2) remodeling enzymes tafazzin and acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1); and 3) outer membrane CL enzymes, mitochondrial phospholipase D and phospholipid scramblase 3 (Plscr3), during chronic contractile activity (CCA)-induced mitochondrial biogenesis and denervation.

Denervation-induced mitochondrial dysfunction and autophagy in skeletal muscle of apoptosis-deficient animals.

Skeletal muscle undergoes remarkable adaptations in response to chronic decreases in contractile activity, such as a loss of muscle mass, decreases in both mitochondrial content and function, as well as the activation of apoptosis. Although these adaptations are well known, questions remain regarding the signaling pathways that mediated these changes. Autophagy is an organelle turnover pathway that could contribute to these adaptations.

Relationship between Sirt1 expression and mitochondrial proteins during conditions of chronic muscle use and disuse.

Sirt1 is a NAD(+)-dependent histone deacetylase that interacts with the regulatory protein of mitochondrial biogenesis PGC-1alpha and is sensitive to metabolic alterations. We assessed whether a strict relationship between the expression of Sirt1, mitochondrial proteins, and PGC-1alpha existed across tissues possessing a wide range of oxidative capabilities, as well as in skeletal muscle subject to chronic use (voluntary wheel running or electrical stimulation for 7 days, 10 Hz; 3 h/day) or disuse (denervation for up to 21 days) in which organelle biogenesis is altered. PGC-1alpha levels were not closely associated with the expression of Sirt1, measured using immunoblotting or via enzymatic deacetylase activity.

Denervation-induced oxidative stress and autophagy signaling in muscle.

Alterations in contractile activity influence the intracellular homeostasis of muscle, which results in adaptations in the performance and the phenotype of this tissue. Denervation is an effective disuse model that functions to change the intracellular environment of muscle leading to a rapid loss in mass, a decrease in mitochondrial content, and an elevation in both proapoptotic protein expression and myonuclear apoptosis. Recent investigations have shown that alternative degradation pathways such as autophagy are activated in conjunction with apoptosis during chronic muscle disuse.

Mitochondria in skeletal muscle: adaptable rheostats of apoptotic susceptibility.

Apoptosis is an essential process that plays a critical role in both tissue development and maintenance. Apoptosis has been shown to be involved in skeletal muscle atrophy resulting from chronic muscular disuse, sarcopenia, and mitochondrial myopathies. Exercise may attenuate some of the proapoptotic adaptations that occur during these conditions.

Effect of prior chronic contractile activity on mitochondrial function and apoptotic protein expression in denervated muscle.

Skeletal muscle is highly adaptable in response to increases and decreases in contractile activity. The purpose of this study was to determine whether the preconditioning of skeletal muscle has a protective effect against subsequent denervation-induced apoptotic protein expression. To investigate this, we chronically stimulated the tibialis anterior and extensor digitorum longus muscles for 7 days (10 Hz, 3 h/day) before 7 days of denervation.

Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle.

Chronic muscle disuse induced by denervation reduces mitochondrial content and produces muscle atrophy. To investigate the molecular mechanisms responsible for these adaptations, we assessed 1) mitochondrial biogenesis- and apoptosis-related proteins and 2) apoptotic susceptibility and cell death following denervation. Rats were subjected to 5, 7, 14, 21, or 42 days of unilateral denervation of the sciatic or peroneal nerve.