# REGULATION OF MEMBRANE MEDIATED MUSCLE DEGENERATION

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 1992 · $123,911

## Abstract

Excessive intracellular Ca accumulation (EICA) is a fundamental
pathogenetic event in muscle degeneration which occurs in
several human disorders such as muscular dystrophy and acute
pancreatitis.  EICA is associated with reduced cellular energy
charge, (Mg) and (K) with increased (Na), (P) and (Zn);
mitochondrial (MIT) & sarcoplasmic reticulum (SR) Ca-
overloading with functional impairments; and cellular necrosis.

The goals of this proposal are: (1) to characterize the CHF-148
strain dystrophic hamsters (DH) as an in vivo model for the study
of membrane mediated EICA and associated pathobiology in
muscle degeneration, (2) to elucidate the mechanism(s) of EICA at
the cellular and subcellular levels, and (3) to evaluate the effects
of ATP-MgCl2, Diltiazem (DTZM), and their combination in the
regulation of EICA in DH.

To achieve these goals, cellular and subcellular total (Ca),
exchangeable Ca pool, uptake and release of 45Ca, and
myoplasmic free (Ca) will be quantitated and correlated at
different stages of muscle degeneration in DH.  Cellular energy
charge, Na, K, Mg, Zn, and P, and plasma P, CK, and LD will also
be determined and correlated with the EICA.  Mitochondrial
coupling, integrity, and purity will be evaluated by the
measurement of RCR, ANT and ATP synthetic activities, long-
chain FFA accumulation, and citrate synthase activity.  SR purity
will be assessed by the rotenone-insensitive NADPH-cytochrome
C-reductase activity.  Evaluation of ultrastructural and
membranous changes in the MIT, SR, and tissue preparations will
be accomplished by EM.  Histologic correlations of tissues such as
% of Ca2+-positive fibers, centronucleated fibers, necrotic fibers,
and fiber splitting will be determined by morphometric analysis.

The pharmacologic regulation of EICA and associated
degenerative changes will be studied for 14 and 56 days in well-
characterized DH by continuous (0.5 ul/hr) subcutaneous infusion
of ATP-MgCl2 (membrane stabilizer and vasodilator), DTZM (Ca-
channel blocker), and by their combination via implanted osmotic
minipumps.  Papavarine, dopamine, and saline infused DH will
serve as the vasodilatory, inotropic, and Ca-channel blocker
controls respectively.  Changes in EICA and all of the above
variables will be correlated during muscle degeneration and
pharmacologic regulation.

The long-term objectives of this study are to provide new
information on the mechanism of membrane mediated EICA; and
more vitally the pharmacologic regulation of intracellular Ca
accumulation and associated pathobiology during muscle
degeneration.

## Key facts

- **NIH application ID:** 3158616
- **Project number:** 5R01AR038540-05
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **SAM.gov UEI:** X1M1PN3KG3E7
- **Principal Investigator:** SYAMAL K BHATTACHARYA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $123,911
- **Award type:** 5
- **Project period:** 1988-04-01 → 1994-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3158616

## Citation

> US National Institutes of Health, RePORTER application 3158616, REGULATION OF MEMBRANE MEDIATED MUSCLE DEGENERATION (5R01AR038540-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3158616. Licensed CC0.

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