Heat shock protein 70 (Hsp70) is a highly conserved and ubiquitous protein that is reported to provide cytoprotection in various cell types and tissues. However, the importance of Hsp70 expression during skeletal muscle atrophy, when Hsp70 levels are significantly decreased, is not known. The current study aimed to determine whether plasmid-mediated overexpression of Hsp70, in the soleus muscle of rats, was sufficient to regulate specific atrophy signaling pathways and attenuate skeletal muscle disuse atrophy. We found that Hsp70 overexpression prevented disuse muscle fiber atrophy and inhibited the increased promoter activities of atrogin-1 and MuRF1. Importantly, the transcriptional activities of Foxo3a and NF-kappaB, which are implicated in the regulation of atrogin-1 and MuRF1, were abolished by Hsp70. These data suggest that Hsp70 may regulate key atrophy genes through inhibiting Foxo3a and NF-kappaB activities during disuse. Indeed, we show that specific inhibition of Foxo3a prevented the increases in both atrogin-1 and MuRF1 promoter activities during disuse. However, inhibition of NF-kappaB did not affect the activation of either promoter, suggesting its requirement for disuse atrophy is through its regulation of other atrophy genes. We conclude that overexpression of Hsp70 is sufficient to inhibit key atrophy signaling pathways and prevent skeletal muscle atrophy.

These experiments tested the hypothesis that a relatively short duration of controlled mechanical ventilation (MV) will impair diaphragmatic maximal specific force generation (specific P(o)) and that this force deficit will be exacerbated with increased time on the ventilator. To test this postulate, adult Sprague-Dawley rats were randomly divided into one of six experimental groups: 1) control (n = 12); 2) 12 h of MV (n = 4); 3) 18 h of MV (n = 4); 4) 18 h of anesthesia and spontaneous breathing (n = 4); 5) 24 h of MV (n = 7); and 6) 24 h of anesthesia and spontaneous breathing (n = 4). MV animals were anesthetized, tracheostomized, and ventilated with room air. Animals in the control group were acutely anesthetized but were not exposed to MV. Animals in two spontaneous breathing groups were anesthetized and breathed spontaneously for either 18 or 24 h. No differences (P > 0.05) existed in diaphragmatic specific P(o) between control and the two spontaneous breathing groups. In contrast, compared with control, all durations of MV resulted in a reduction (P < 0.05) in diaphragmatic specific tension at stimulation frequencies ranging from 15 to 160 Hz. Furthermore, the MV-induced decrease in diaphragmatic specific P(o) was time dependent, with specific P(o) being approximately 18 and approximately 46% lower (P < 0.05) in animals mechanically ventilated for 12 and 24 h, respectively. These data support the hypothesis that relatively short-term MV impairs diaphragmatic contractile function and that the magnitude of MV-induced force deficit increases with time on the ventilator.

Heat stress attenuates skeletal muscle atrophy in hindlimbunweighted rats. J. Appl. Physiol. 88: 359-363, 2000.-This study tested the hypothesis that elevation of heat stress proteins by whole body hyperthermia is associated with a decrease in skeletal muscle atrophy induced by reduced contractile activity (i.e., hindlimb unweighting). Female adult rats (6 mo old) were assigned to one of four experimental groups (n ϭ 10/group): 1) sedentary control (Con), 2) heat stress (Heat), 3) hindlimb unweighting (HLU), or 4) heat stress before hindlimb unweighting (HeatϩHLU). Animals in the Heat and HeatϩHLU groups were exposed to 60 min of hyperthermia (colonic temperature ϳ41.6°C). Six hours after heat stress, both the HLU and HeatϩHLU groups were subjected to hindlimb unweighting for 8 days. After hindlimb unweighting, the animals were anesthetized, and the soleus muscles were removed, weighed, and analyzed for protein content and the relative levels of heat shock protein 72 (HSP72). Compared with control and HLU animals, the relative content of HSP72 in the soleus muscle was significantly elevated (P Ͻ 0.05) in both the Heat and HeatϩHLU animals. Although hindlimb unweighting resulted in muscle atrophy in both the HLU and HeatϩHLU animals, the loss of muscle weight and protein content was significantly less (P Ͻ 0.05) in the HeatϩHLU animals. These data demonstrate that heat stress before hindlimb unweighting can reduce the rate of disuse muscle atrophy. We postulate that HSP70 and/or other stress proteins play a role in the control of muscle atrophy induced by reduced contractile activity. non-weight bearing; hindlimb suspension; hyperthermia; heat shock protein 70; protein synthesis; soleus muscle IT IS WELL KNOWN THAT DECREASING the load on a skeletal muscle results in muscle atrophy (1,8,(14)(15)(16). Studies using a rodent model of muscle disuse atrophy (i.e., hindlimb unweighting via tail suspension) indicate that the initial loss of muscle protein is primarily due to a decrease in the rate of protein synthesis (14). Subsequent atrophy then occurs by increased rates of protein degradation (14). It has been suggested that the initial decrease in protein synthesis during non-weightbearing activity is a result of a reduced rate of nascent polypeptide chain elongation at the ribosomal level (7). Because the inducible form of the 70-kDa heat shock protein (HSP72) plays an important role in chaperoning nascent peptides during translation, it has been postulated that a decrease in cellular HSP72 levels in myocytes is a potential mechanism to explain the decreased translation observed during muscle disuse (8). Hence, it is conceivable that elevation of cellular HSP72 levels could serve as a countermeasure to attenuate the disuse-induced reduction in protein synthesis.It also seems possible that HSP72 can play a protective role in the prevention of muscle protein degradation during periods of reduced contractile activity. A conceivable link between HSP72 and reduced protein degradation in muscle is as follows. Recent evid...

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In recent years, an increasing number of studies have demonstrated that a myopathy is present, contributes, and, to a certain extent, determines the pathogenesis of peripheral arterial occlusive disease. These works provide evidence that a state of repetitive cycles of exercise-induced ischemia followed by reperfusion at rest operates in patients with peripheral arterial occlusive disease and mediates a large number of structural and metabolic changes in the muscle, resulting in reduced strength and function. The key players in this process appear to be defective mitochondria that, through multilevel failure in their roles as energy, oxygen radical species, and apoptosis regulators, produce and sustain a progressive decline in muscle performance. In this 2-part review, the currently available evidence that characterizes the nature and mechanisms responsible for this myopathy is highlighted. In part 1, the functional and histomorphological characteristics of the myopathy were reviewed, and the main focus was on the biochemistry and bioenergetics of its mitochondriopathy. In part 2, accumulating evidence that oxidative stress related to ischemia reperfusion is probably the major operating mechanism of peripheral arterial occlusive disease myopathy is reviewed. Important new findings of a possible neuropathy and a shift in muscle fiber type are also reviewed. Learning more about these mechanisms will enhance our understanding of the degree to which they are preventable and treatable.