Exercise-induced muscle injury: a calpain hypothesis.

It is well established that periods of increased contractile activity result in significant changes in muscle structure and function. Such morphological changes as sarcomeric Z-line disruption and sarcoplasmic reticulum vacuolization are characteristic of exercise-induced muscle injury. While the precise mechanism(s) underlying the perturbations to muscle following exercise remains to be elucidated, it is clear that disturbances in Ca2+ homeostasis and changes in the rate of protein degradation occur. The resulting elevation in intracellular [Ca2+] activates the non-lysosomal cysteine protease, calpain. Because calpain cleaves a variety of protein substrates including cytoskeletal and myofibrillar proteins, calpain-mediated degradation is thought to contribute to the changes in muscle structure and function that occur immediately following exercise. In addition, calpain activation may trigger the adaptation response to muscle injury. The purpose of this paper is to: (i) review the chemistry of the calpain-calpastatin system; (ii) provide evidence for the involvement of the non-lysosomal, calcium-activated neutral protease (calpain) in the response of skeletal muscle protein breakdown to exercise (calpain hypothesis); and (iii) describe the possible involvement of calpain in the inflammatory and regeneration response to exercise.

Dietary L-glutamine does not improve lymphocyte metabolism or function in exercise-trained rats.

Decreased glutamine availability is proposed as a mechanism for changes in immune function with intense exhaustive exercise. Less is known about the immunomodulatory effects of regular nonexhaustive exercise. To determine the effects of low intensity regular exercise and dietary glutamine supplementation on plasma glutamine concentrations, lymphocyte metabolism, and immune function, male (278 +/- 5 g) and female (182 +/- 1 g) Sprague-Dawley Buffalo rats were fed nutritionally complete casein-based semi-purified diets +/- 2% w/w glutamine. Rats were trained (21 d), as confirmed by higher (P < 0.05) succinate dehydrogenase activity in soleus muscle, to swim 2 or 4 h.d-1 or remained sedentary. Exercise lowered plasma concentrations of tryptophan, glutamate, methionine, alanine, threonine, aspartate, asparagine, and ornithine and increased the lysine concentration (P < 0.05). Neither diet nor exercise altered plasma glutamine concentrations, lymphocyte phenotypes in spleen, or the in vitro rates of splenocyte energy metabolism (production of glucose and glutamine metabolites or ATP concentrations in the incubation media). Compared with nonsupplemented rats, splenic cytolytic activity (lysis of 51Cr labeled YAC-1 cells) was reduced (P < 0.05) in the glutamine-supplemented exercising group. Under these conditions, glutamine supplementation does not appear to provide any added benefit to the exercise-trained animal.

Dietary L-glutamine supplementation reduces the growth of the Morris Hepatoma 7777 in exercise-trained and sedentary rats.

Dietary glutamine supplementation and exercise have been reported independently to enhance immune function and reduce tumor growth. We study the effect of both of these interventions on the growth of the Morris Hepatoma 7777, implanted in 59 female Sprague-Dawley Buffalo rats. Rats were fed a nutritionally complete, purified diet with or without L-glutamine 20 g/kg diet and randomized to swim 3 h/d or to remain sedentary. After 14 d, the mean tumor weight of glutamine-supplemented rats was lower (P < 0.0001) than that of unsupplemented rats (5.8 +/- 0.4 vs. 8.7 +/- 0.5 g, respectively). Exercise did not alter tumor growth. Glutamine supplementation increased [3H] thymidine incorporation by splenocytes incubated with Concanavalin A and the proportion of natural killer cells in spleen, but not cytotoxic activity against YAC-1 cells. Glutamine supplementation did not alter glutamine concentrations in plasma (691 +/- 12 mumol/L) or soleus muscle (5328 +/- 102 pmol/mg) but resulted in higher (P < 0.004) plasma concentrations of leucine, isoleucine and valine, precursors of glutamine. Splenocytes from exercised rats had a higher (P < 0.001) mitogen response than those from sedentary rats. Isolated tumor cells demonstrated high rates of non-oxidative glucose and glutamine metabolism and consumption of glutamine, tryptophan and methionine. However, neither diet nor exercise significantly affected glucose or glutamine metabolism by tumor cells. The precise mechanism of tumor growth suppression by oral glutamine supplementation is not clear but may be related to changes in substrate availability, improved tumor-directed natural killer cytotoxic activity or a faster response to an immune challenge.

Reduced splenocyte metabolism and immune function in rats implanted with the Morris Hepatoma 7777.

Although the immune system is important in antitumor defense, little is know about the immune response during progressive tumor growth. Sprague-Dawley rats (171 +/- 3g) of the Buffalo strain were implanted with the Morris Hepatoma 7777 ([MH 7777] a poorly differentiated, rapidly growing tumor) and killed either 2 (T2) or 3 (T3) weeks postimplantation when the tumor weighed 3.0 +/- 0.4 and 14 +/- 1 g, respectively. Splenocytes were isolated and their phenotypes, metabolism (metabolite production from glucose and glutamine), proliferative response ([3H]thymidine incorporation in response to polyclonal mitogens), and natural killer (NK) cytotoxicity (lysis of YAC-1 cells) were determined. Five rats were killed with the T2 group to serve as non-tumor-bearing controls (T0). Food intake and nontumor body weight decreased (P < .01) 14 days after tumor implantation. There was a progressive decrease (T3 < T2 < T0) in splenic mitogen responses (P < .05) and plasma essential and nonessential amino acid concentrations (P < .05). Compared with T0, NK cytotoxic activity was significantly (P < .05) lower at T2 and higher at T3. The presence of the tumor at both T2 and T3 resulted in lower production of metabolites from glucose and glutamine by splenocytes. The proportion of CD8+ cells was lower (P < .05) and the proportion of B cells and macrophages higher (P < .05) in spleens from tumor-bearing rats. In conclusion, the presence of even a small tumor burden (1.4% of body weight) significantly altered the host's immune function and metabolism. A larger tumor burden (6% of body weight) increased NK cytotoxic activity and further reduced cell-mediated immune function.